BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL2101150001?filename=Corral_ThIL17diff_15jan2021.sbmlprimaryOK200Denis ThieffryNon-curatedlogical modelL3V1https://www.ebi.ac.uk/biomodels/MODEL2101150001falseBioModelsSBMLModelsMultiomicsCorral2021 Interplay between SMAD2 and STAT5A regulating IL 17A/F expression in Th cells.2021MODEL2101150001Karla Fabiola Corral-Jara, Camille Chauvin, Wassim Abou-Jaoud\'e, Maximilien Grandclaudon, Aur\'elien Naldi, Vassili Soumelis, Denis ThieffryKarla Fabiola Corral-Jara10.1186/s43556-021-00034-3,
. 1, 2.
Computational Systems Biology Team, Institut de Biologie de l’École Normale Supérieure, CNRS UMR8197, INSERM U1024, École Normale Supérieure, PSL Université, 75005 Paris, Francedenis.thieffry@ens.fr10.1186/s43556-021-00034-3Ecole Normale SupérieureThe Tec family tyrosine kinase (Itk), is a key component of the TCR signaling pathway. Biochemical studies have shown that Itk activation requires recruitment of Itk to the membrane via its pleckstrin homology domain, phosphorylation of Itk by the Src kinase, Lck, and binding of Itk to the SLP-76/LAT adapter complex. However, the regulation of Itk enzymatic activity by Itk domain interactions is not yet well understood. In this study, we show that full-length Itk self-associates in an intermolecular fashion. Using this information, we have designed an Itk variant that exhibits reduced self-association but maintains normal binding to exogenous ligands via each of its regulatory domains. When expressed in insect cells, the Itk substrate phospholipase Cgamma1 is phosphorylated more efficiently by the Itk variant than by wild-type Itk. Furthermore, expression of the Itk variant in primary murine T cells induced higher ERK activation and increased calcium flux following TCR stimulation compared with that of wild-type Itk. Our results indicate that the Tec kinase Itk is negatively regulated by intermolecular clustering and that disruption of this clustering leads to increased Itk kinase activity following TCR stimulation.TGFβ is the quintessential cytokine of T cell homeostasis. TGFβ signaling is required for the efficient differentiation and maintenance of CD4(+)FOXP3(+) T cells that inhibit immune responses. Conversely, in conjunction with the inflammatory cytokine IL-6, TGFβ promotes Th17 cell differentiation. The mechanism by which TGFβ signals synergize with IL-6 to generate inflammatory versus immunosuppressive T cell subsets is unclear. TGFβ signaling activates receptor SMADs, SMAD2 and SMAD3, which associate with a variety of nuclear factors to regulate gene transcription. Defining relative contributions of distinct SMAD molecules for CD4 T cell differentiation is critical for mapping the versatile intracellular TGFβ-signaling pathways that tailor TGFβ activities to the state of host interaction with pathogens. We show here that SMAD2 is essential for Th17 cell differentiation and that it acts in part by modulating the expression of IL-6R on T cells. Although mice lacking SMAD2 specifically in T cells do not develop spontaneous lymphoproliferative autoimmunity, Smad2-deficient T cells are impaired in their response to TGFβ in vitro and in vivo, and they are more pathogenic than controls when transferred into lymphopenic mice. These results demonstrate that SMAD2 is uniquely essential for TGFβ signaling in CD4(+) T effector cell differentiation.Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Studies on somatic hypermutation of the antigen binding region, receptor expression levels and signal capacity have all linked BCR on CLL cells to disease prognosis. Our previous work showed that the src-family kinase Lck is a targetable mediator of BCR signalling in CLL cells, and that variance in Lck expression associated with ability of BCR to induce signal upon engagement. This latter finding makes Lck similar to ZAP70, another T-cell kinase whose aberrant expression in CLL cells also associates with BCR signalling capacity, but also different because ZAP70 is not easily pharmacologically targetable. Here we describe a robust method of measuring Lck expression in CLL cells using flow cytometry. However, unlike ZAP70 whose expression in CLL cells predicts prognosis, we find Lck expression and disease outcome in CLL are unrelated despite observations that its inhibition produces effects that biologically resemble the egress phenotype taken on by CLL cells treated with idelalisib. Taken together, our findings provide insight into the pathobiology of CLL to suggest a more complex relationship between expression of molecules within the BCR signalling pathway and disease outcome.T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.IL-17-producing Th (Th17) comprise a distinct lineage of pro-inflammatory Th that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor beta (TGFbeta) induces naive CD4+ T cells to generate Th17, which also requires expression of the IL-6/TGFbeta target RORgammat. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4+ T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into Th17, while CD4+ T cells whose mutant gp130 transduces the STAT3 signal only generated Th17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of Th17. Moreover, we found that gp130-STAT3 pathway is essential for Th17 development and for the expression of RORgammat by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6-gp130-STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of Th17 by activating the T cell gp130-STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted Th17-mediated immune responses including autoimmune diseases.MyD88 and IL-1R-associated kinase 1 (IRAK-1) play crucial roles as adaptor molecules in signal transduction of the TLR/IL-1R superfamily, and it is known that expression of these proteins leads to the activation of NF-kappaB in a TNFR-associated factor 6 (TRAF6)-dependent manner. We found in this study, however, that a dominant-negative mutant of TRAF6, lacking the N-terminal RING and zinc-finger domain, did not inhibit IRAK-1-induced activation of NF-kappaB in human embryonic kidney 293 cells, although the TRAF6 mutant strongly suppressed the MyD88-induced activation. The dominant-negative mutant of TRAF6 did not affect the IRAK-1-induced activation, regardless of the expression level of IRAK-1. In contrast, small interfering RNA silencing of TRAF6 expression inhibited MyD88-induced and IRAK-1-induced activation, and supplementation with the TRAF6 dominant-negative mutant did not restore the IRAK-1-induced activation. Expression of IRAK-1, but not MyD88, induced the oligomerization of TRAF6, and IRAK-1 and the TRAF6 dominant-negative mutant were associated with TRAF6. These results indicate that TRAF6 is involved but with different mechanisms in MyD88-induced and IRAK-induced activation of NF-kappaB and suggest that TRAF6 uses a distinctive mechanism to activate NF-kappaB depending on signals.Recent work has identified a new subset of effector T cells that produces interleukin (IL)-17 known as T helper 17 (Th17) cells, which is involved in the pathophysiology of inflammatory diseases and is thought to be developmentally related to regulatory T (Treg) cells. Because of its importance for Treg cells, we examined the role of IL-2 in Th17 generation and demonstrate that a previously unrecognized aspect of IL-2 function is to constrain IL-17 production. Genetic deletion or antibody blockade of IL-2 promoted differentiation of the Th17 cell subset. Whereas STAT3 appeared to be a key positive regulator of RORgammat and IL-17 expression, absence of IL-2 or disruption of its signaling by deletion of the transcription factor STAT5 resulted in enhanced Th17 cell development. We conclude that in addition to the promotion of activation-induced cell death of lymphocytes and the generation of Treg cells, inhibition of Th17 polarization appears to be an important function of IL-2.Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor κB (NF-κB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-κB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-κB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-κB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs.Exactly how ligand binding 'triggers' T cell receptor (TCR) phosphorylation is unclear. It has been proposed that ligand engagement by the TCR somehow activates the Src kinase Lck, which in turn phosphorylates the receptor. Recent data, however, suggest instead that a significant fraction of the Lck in resting T cells is already activated and that the proportion of active Lck does not change during the early stages of T cell activation. We argue that, caveats notwithstanding, these new observations offer support for the 'kinetic-segregation' model of TCR triggering, which involves spatial reorganization of signalling proteins upon ligand binding and requires a fraction of Lck to be active in resting T cells.Being one of the key kinases downstream of Toll-like receptors, IRAK1 has initially thought to be responsible for NFkappaB activation. Yet IRAK1 knock-out mice still exhibit NFkappaB activation upon lipopolysaccharide (LPS) challenge, suggesting that IRAK1 may play other un-characterized function. In this report, we show that IRAK1 is mainly involved in Stat3 activation and subsequent interleukin-10 (IL-10) gene expression. Splenocytes from IRAK1-deficient mice fail to exhibit LPS-induced Stat3 serine phosphorylation and IL-10 gene expression yet still maintain normal IL-1beta gene expression upon LPS challenge. Mechanistically, we observe that IRAK1 modification upon LPS challenge leads to its modification, nuclear distribution, and interaction with Stat3. IRAK1 can directly use Stat3 as a substrate and cause Stat3 serine 727 phosphorylation. In addition, nuclear IRAK1 binds directly with IL-10 promoter in vivo upon LPS treatment. Atherosclerosis patients usually have elevated serum IL-10 levels. We document here that IRAK1 is constitutively modified and localized in the nucleus in the peripheral blood mononuclear cells from atherosclerosis patients. These observations reveal the mechanism for the novel role of IRAK1 in the complex Toll-like receptor signaling network and indicate that IRAK1 regulation may be intimately linked with the pathogenesis and/or resolution of atherosclerosis.T cell-specific deletion of Blimp-1 causes abnormal T cell homeostasis and function, leading to spontaneous, fatal colitis in mice. Herein we explore the role of Blimp-1 in Th1/Th2 differentiation. Blimp-1 mRNA and protein are more highly expressed in Th2 cells compared with Th1 cells, and Blimp-1 attenuates IFN-gamma production in CD4 cells activated under nonpolarizing conditions. Although Blimp-1-deficient T cells differentiate normally to Th2 cytokines in vitro, Blimp-1 is required in vivo for normal Th2 humoral responses to NP-KLH (4-hydroxy-3-nitrophenylacetyl/keyhole lymphocyte hemocyanin) immunization. Lack of Blimp-1 in CD4 T cells causes increased IFN-gamma, T-bet, and Bcl-6 mRNA. By chromatin immunoprecipitation we show that Blimp-1 binds directly to a distal regulatory region in the ifng gene and at multiple sites in tbx21 and bcl6 genes. Our data provide evidence that Blimp-1 functions in Th2 cells to reinforce Th2 differentiation by repressing critical Th1 genes.Interferon regulatory factor 4 (IRF4) is a transcription factor that is expressed in hematopoietic cells and plays pivotal roles in the immune response. Originally described as a lymphocyte-specific nuclear factor, IRF4 promotes differentiation of naïve CD4(+) T cells into T helper 2 (Th2), Th9, Th17, or T follicular helper (Tfh) cells and is required for the function of effector regulatory T (eTreg) cells. Moreover, IRF4 is essential for the sustained differentiation of cytotoxic effector CD8(+) T cells, for CD8(+) T-cell memory formation, and for differentiation of naïve CD8(+) T cells into IL-9-producing (Tc9) and IL-17-producing (Tc17) CD8(+) T-cell subsets. In this review, we focus on recent findings on the role of IRF4 during the development of CD4(+) and CD8(+) T-cell subsets and the impact of IRF4 on T-cell-mediated immune responses in vivo.CD4(+) T helper cells are classical but constantly reinterpreted T-cell subset, playing critical roles in a diverse range of inflammatory responses or diseases. Depending on the cytokines they release and the immune responses they mediate, CD4(+) T cells are classically divided into two major cell populations: Th1 and Th2 cells. However, recent studies challenged this Th1/Th2 paradigm by discovering several T-helper cell subsets with specific differentiation program and functions, including Th17 cells, Treg cells, and Tfh cells. In this chapter, we summarize the current understanding and recent progresses on the Th17 lineage differentiation and its effector impacts on variety of inflammatory responses or disease pathogenesis.The interleukin 2 receptor alpha chain (IL-2Ralpha) is a component of high affinity IL-2 receptors and thus critically regulates T cell growth and other lymphoid functions. Five positive regulatory regions together control lineage-restricted and activation-dependent IL-2Ralpha induction in response to antigen and IL-2. We now show that TGF-beta cooperates with T cell receptor (TCR) signaling to increase IL-2Ralpha gene expression. Moreover, we identify a sixth positive regulatory region that regulates IL-2Ralpha expression in cells treated with anti-CD3 + anti-CD28 as well as TGF-beta and show that this region contains binding sites for Smad3, AP-1, and cAMP-responsive element-binding protein/ATF proteins. The importance of Smad complexes is indicated by impaired IL-2Ralpha induction by TGF-beta in CD4+ T cells from both Smad3-/- and Smad4-/- mice. Thus, we have identified a novel positive regulatory region in the IL-2Ralpha gene that mediates TGF-beta-dependent induction of the gene. These findings have implications related to IL-2Ralpha expression on activated T cells and regulatory T cells.TAK1, a member of the mitogen-activated kinase kinase kinase family, is activated in vivo by various cytokines, including interleukin-1 (IL-1), or when ectopically expressed together with the TAK1-binding protein TAB1. However, this molecular mechanism of activation is not yet understood. We show here that endogenous TAK1 is constitutively associated with TAB1 and phosphorylated following IL-1 stimulation. Furthermore, TAK1 is constitutively phosphorylated when ectopically overexpressed with TAB1. In both cases, dephosphorylation of TAK1 renders it inactive, but it can be reactivated by preincubation with ATP. A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192.T cell antigen receptor (TCR) stimulation induces tyrosine phosphorylation of many intracellular proteins, including the proto-oncogene Vav, which is expressed exclusively in hematopoietic and trophoblast cells. Vav is critical for lymphocyte development and activation. Overexpression of Vav in Jurkat T cells leads to potentiation of TCR-mediated IL-2 gene activation. However, the biochemical function of Vav is unknown. Here, we demonstrate that the major induced tyrosine phosphoprotein associated with Vav is the hematopoietic cell-specific SLP-76. The Vav SH2 domain is required for this interaction and for TCR-mediated Vav tyrosine phosphorylation. Similar to Vav, overexpression of SLP-76 markedly potentiates TCR-mediated NF-AT and IL-2 gene activation. Furthermore, overexpression of both Vav and SLP-76 synergistically induces basal and TCR-stimulated NF-AT activation. These results suggest that a signaling complex containing Vav and SLP-76 plays an important role in lymphocyte activation.In this study we demonstrated that CD4(+) T cells from STAT4(-/-) mice exhibit reduced IL-12R expression and poor IL-12R signaling function. This raised the question of whether activated STAT4 participates in Th1 cell development mainly through its effects on IL-12 signaling. In a first approach to this question we determined the capacity of CD4(+) T cells from STAT4(-/-) bearing an IL-12Rbeta2 chain transgene (and thus capable of normal IL-12R expression and signaling) to undergo Th1 differentiation when stimulated by Con A and APCs. We found that such cells were still unable to exhibit IL-12-mediated IFN-gamma production. In a second approach to this question, we created Th2 cell lines (D10 cells) transfected with STAT4-expressing plasmids with various tyrosine-->phenylalanine mutations and CD4(+) T cell lines from IL-12beta2(-/-) mice infected with retroviruses expressing similarly STAT4 mutations that nevertheless express surface IL-12Rbeta2 chains. We then showed that constructs that were unable to support STAT4 tyrosine phosphorylation (in D10 cells) as a result of mutation were also incapable of supporting IL-12-induced IFN-gamma production (in IL-12Rbeta2(-/-) cells). Thus, by two complementary approaches we demonstrated that activated STAT4 has an essential downstream role in Th1 cell differentiation that is independent of its role in the support of IL-12Rbeta2 chain signaling. This implies that STAT4 is an essential element in the early events of Th1 differentiation.Secretion of the immunosuppressive cytokine interleukin (IL) 10 by effector T cells is an essential mechanism of self-limitation during infection. However, the transcriptional regulation of IL-10 expression in proinflammatory T helper (Th) 1 cells is insufficiently understood. We report a crucial role for the transcriptional regulator Blimp-1, induced by IL-12 in a STAT4-dependent manner, in controlling IL-10 expression in Th1 cells. Blimp-1 deficiency led to excessive inflammation during Toxoplasma gondii infection with increased mortality. IL-10 production from Th1 cells was strictly dependent on Blimp-1 but was further enhanced by the synergistic function of c-Maf, a transcriptional regulator of IL-10 induced by multiple factors, such as the Notch pathway. We found Blimp-1 expression, which was also broadly induced by IL-27 in effector T cells, to be antagonized by transforming growth factor (TGF) β. While effectively blocking IL-10 production from Th1 cells, TGF-β shifted IL-10 regulation from a Blimp-1-dependent to a Blimp-1-independent pathway in IL-27-induced Tr1 (T regulatory 1) cells. Our findings further illustrate how IL-10 regulation in Th cells relies on several transcriptional programs that integrate various signals from the environment to fine-tune expression of this critical immunosuppressive cytokine.Signaling via the Akt/mammalian target of rapamycin pathway influences CD4(+) T cell differentiation; low levels favor regulatory T cell induction and high levels favor Th induction. Although the lipid phosphatase phosphatase and tensin homolog (PTEN) suppresses Akt activity, the control of PTEN activity is poorly studied in T cells. In this study, we identify multiple mechanisms that regulate PTEN expression. During Th induction, PTEN function is suppressed via lower mRNA levels, lower protein levels, and an increase in C-terminal phosphorylation. Conversely, during regulatory T cell induction, PTEN function is maintained through the stabilization of PTEN mRNA transcription and sustained protein levels. We demonstrate that differential Akt/mammalian target of rapamycin signaling regulates PTEN transcription via the FoxO1 transcription factor. A mathematical model that includes multiple modes of PTEN regulation recapitulates our experimental findings and demonstrates how several feedback loops determine differentiation outcomes. Collectively, this work provides novel mechanistic insights into how differential regulation of PTEN controls alternate CD4(+) T cell fate outcomes.PKCtheta plays an essential role in activation of mature T cells via stimulation of AP-1 and NF-kappaB, and is known to selectively translocate to the immunological synapse in antigen-stimulated T cells. Recently, we reported that a Vav/Rac pathway which depends on actin cytoskeleton reorganization mediates selective recruitment of PKCtheta to the membrane or cytoskeleton and its catalytic activation by anti-CD3/CD28 costimulation. Because this pathway acted selectively on PKCtheta, we addressed here the question of whether the translocation and activation of PKCtheta in T cells is regulated by a unique pathway distinct from the conventional mechanism for PKC activation, i.e., PLC-mediated production of DAG. Using three independent approaches, i.e., a selective PLC inhibitor, a PLCgamma1-deficient T cell line, or a dominant negative PLCgamma1 mutant, we demonstrate that CD3/CD28-induced membrane recruitment and COOH-terminal phosphorylation of PKCtheta are largely independent of PLC. In contrast, the same inhibitory strategies blocked the membrane translocation of PKCalpha. Membrane or lipid raft recruitment of PKCtheta (but not PKCalpha) was absent in T cells treated with phosphatidylinositol 3-kinase (PI3-K) inhibitors or in Vav-deficient T cells, and was enhanced by constitutively active PI3-K. 3-phosphoinositide-dependent kinase-1 (PDK1) also upregulated the membrane translocation of PKCtheta;, but did not associate with it. These results provide evidence that a nonconventional PI3-K- and Vav-dependent pathway mediates the selective membrane recruitment and, possibly, activation of PKCtheta in T cells.Interleukin-2 was discovered in 1976 as a T-cell growth factor. It was the first type I cytokine cloned and the first for which a receptor component was cloned. Its importance includes its multiple actions, therapeutic potential, and lessons for receptor biology, with three components differentially combining to form high, intermediate, and low-affinity receptors. IL-2Ralpha and IL-2Rbeta, respectively, are markers for double-negative thymocytes and regulatory T-cells versus memory cells. gamma(c), which is shared by six cytokines, is mutated in patients with X-linked severe-combined immunodeficiency. We now cover an under-reviewed area-the regulation of genes encoding IL-2 and IL-2R components, with an effort to integrate/explain this knowledge.The expression of the murine interleukin (IL)-2 receptor alpha chain/CD25 is strongly induced at the transcriptional level after T cell activation. We show here that nuclear factor of activated T cell (NF-AT) factors are involved in the control of CD25 promoter induction in T cells. NF-ATp and NF-ATc bind to two sites around positions -585 and -650 located upstream of the proximal CD25 promoter. Immediately 3' from these NF-AT motifs, nonconsensus sites are located for the binding of AP-1-like factors. Mutations of sites that suppress NF-AT binding impair the induction and strong NF-ATp-mediated transactivation of the CD25 promoter in T cells. In T lymphocytes from NF-ATp-deficient mice, the expression of CD25 is severely impaired, leading to a delayed IL-2 receptor expression after T cell receptor (TCR)/CD3 stimulation. Our data indicate an important role for NF-AT in the faithful expression of high affinity IL-2 receptors and a close link between the TCR-mediated induction of IL-2 and IL-2 receptor alpha chain promoters, both of which are regulated by NF-AT factors.Regulatory T cells (T(reg) cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T(eff) cell) function and gain of suppressive activity by T(reg) cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T(reg) cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3' untranslated region. Release of SATB1 from the control of Foxp3 in T(reg) cells caused loss of suppressive function, establishment of transcriptional T(eff) cell programs and induction of T(eff) cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T(reg) cell functionality.Study of the development of distinct CD4(+) T-cell subsets from naive precursors continues to provide excellent opportunities for dissection of mechanisms that control lineage-specific gene expression or repression. Whereas it had been thought that the induction of transcription networks that control T-lineage commitment were highly stable, reinforced by epigenetic processes that confer heritability of functional phenotypes by the progeny of mature T cells, recent findings support a more dynamic view of T-lineage commitment. Here, we highlight advances in the mapping and functional characterization of cis elements in the Ifng locus that have provided new insights into the control of the chromatin structure and transcriptional activity of this signature T-helper 1 cell gene. We also examine epigenetic features of the Ifng locus that have evolved to enable its reprogramming for expression by other T-cell subsets, particularly T-helper 17 cells, and contrast features of the Ifng locus with those of the Il17a-Il17f locus, which appears less promiscuous.Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) and Ras proteins are involved in signalling pathways originating at the plasma membrane. The localisation and metabolism of PI(4,5)P(2) was studied in Jurkat T cells using fluorescence microscopic imaging with EGFP-tagged and antibody probes. Software was developed to objectively quantitate colocalisation and was used to show that plasma membrane PI(4,5)P(2) was enriched in lipid raft-containing patches of GM1 ganglioside, formed by crosslinking cholera toxin B-subunit (CT-B). The PI(4,5)P(2) metabolites phosphatidylinositol 3,4,5-trisphosphate and diacylglycerol appeared in plasma membrane CT-B-GM1 patches upon induction of signalling. Transferrin receptor and the CD45 tyrosine phosphatase did not colocalise with CT-B-GM1 patches, whereas the tyrosine kinase Lck, the scaffolding protein LAT, and endogenous Ras proteins did partially colocalise with CT-B-GM1 patches as did transfected EGFP-K-Ras(4B) and EGFP-H-Ras. The results demonstrate that T-cell PI(4,5)P(2) metabolism is occurring in GM1-enriched domains and that Ras proteins are present in these domains in vivo.Interleukin-17 (IL-17)-producing helper T (TH) cells, named as TH(IL-17), TH17, or inflammatory TH (THi), have been recently identified as a novel effector lineage. However, how cytokine signals mediate THi differentiation is unclear. We found that IL-6 functioned to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi generation. STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired in STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor gamma-T (RORgamma t), a THi-specific transcriptional regulator; STAT3 deficiency impaired RORgamma t expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3). Our data thus demonstrate a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression.STAT1 and STAT3 are the main mediators of the signaling of interferons (IFNs) and of gp130 cytokines, respectively. Neoplastic T lymphocytes frequently become resistant to the IFN-gamma/STAT1 apoptotic pathway, often because of the downregulation of the IFN-gammaR2 receptor chain. Many studies suggest that cross-regulation between different STATs, in particular between STAT1 and STAT3, may profoundly affect cytokine/growth factor signaling. Here, the function of STAT3 in the negative regulation of STAT1 apoptotic pathway was investigated by RNA interference-mediated STAT3 silencing in human malignant T lymphocytes. In STAT3-depleted cells, interleukin (IL)-6 acquired the capacity to induce apoptosis, correlating with prolonged STAT1 activation and the induction of major histocompatibility complex (MHC) class I expression. In contrast, in the absence of STAT3, IFN-gamma could slightly enhance apoptosis but its ability to induce MHC class I expression was unchanged. Accordingly, IL-6, but not IFN-gamma, could significantly impair the in vivo growth of STAT3-depleted human neoplastic T lymphocytes transplanted into severe combined immunodeficient mice. Therefore, treatment with IL-6 and simultaneous STAT3 silencing may represent a potential therapeutic approach to control the expansion of IFN-gamma-unresponsive neoplastic T cells.Myeloid differentiation primary response protein 88 (MyD88) is classically known as an adaptor, linking TLR and IL-1R to downstream signaling pathways in the innate immune system. In addition to its role in innate immune cells, MyD88 has been shown to play an important role in T cells. How MyD88 regulates helper T-cell differentiation remains largely unknown, however. Here we demonstrate that MyD88 is an important regulator of IL-17-producing CD4(+) T helper cells (Th17) cell proliferation. MyD88-deficient CD4(+) T cells showed a defect in Th17 cell differentiation, but not in Th1 cell or Th2 cell differentiation. The impaired IL-17 production from MyD88-deficient CD4(+) T cells is not a result of defective RAR-related orphan receptor γt (RORγt) expression. Instead, MyD88 is essential for sustaining the mammalian target of rapamycin (mTOR) activation necessary to promote Th17 cell proliferation by linking IL-1 and IL-23 signaling. MyD88-deficient CD4(+) T cells showed impaired mTOR activation and, consequently, reduced Th17 cell proliferation. Importantly, the absence of MyD88 in T cells ameliorated disease in the experimental autoimmune encephalomyelitis model. Taken together, our results demonstrate that MyD88 has a dual function in Th17 cells by delivering IL-1 signaling during the early differentiation stage and integrating IL-23 signaling to the mTOR complex to expand committed Th17 cells.Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome-wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORγt, STAT-3, and p300 at the Il23r, Il17a/f, and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORγt to activate the Th17 inflammatory program.Mitogen-activated protein kinase kinase kinase (MEKK1) is a serine-threonine kinase that regulates sequential protein kinase pathways involving stress-activated protein kinases and mitogen-activated protein kinases. MEKK1 is activated in response to growth factor stimulation of cells and by expression of activated Ras. We demonstrate that the kinase domain of MEKK1 (MEKKCOOH) binds to GST-RasV12 in a GTP-dependent manner. Purified bacterially expressed MEKKCOOH binds to GST-RasV12(GTP gamma S) (GTP gamma S is guanosine 5'-3-O-(thio)triphosphate), demonstrating a direct interaction of the two proteins. A Ras effector domain peptide blocks the binding of MEKKCOOH to GST-RasV12(GTP gamma S). MEKKCOOH complexed with GST-RasV12(GTP gamma S) is capable of phosphorylating MEK1. These findings indicate that MEKK1 directly binds Ras.GTP. Thus, Ras interacts with protein kinases of both the Raf and MEKK families.T-cell activation in response to interleukin-12 (IL-12) is mediated through signaling events that include the tyrosine phosphorylation of STAT4. IL-12 responsiveness and the ability of IL-12 to activate STAT4 is different in T cells induced to differentiate into a Th1 or Th2 phenotype. In this report, we show that STAT5, STAT1alpha, and STAT1beta, in addition to STAT4, are tyrosine phosphorylated in response to IL-12 in phytohemagglutinin (PHA)-activated human T cells. To understand how the activation of these STATs contributes to T-cell IL-12 responsiveness, we analyzed the IL-12-induced activation of STAT5 and STAT1 in T cells stimulated to undergo Th1 or Th2 differentiation. The IL-12-induced tyrosine phosphorylation of STAT5 and STAT1, but not STAT4, is augmented in T cells activated into Th1 cells with PHA + interferon-gamma (IFN-gamma) compared with T cells activated with PHA alone. STAT5 DNA binding induced by IL-12 is also augmented in T cells activated with PHA + IFN-gamma compared with T cells activated with PHA alone, whereas STAT4 DNA binding is not increased. In contrast, the IL-12-induced activation of these STATs is inhibited in T cells activated into Th2 cells with PHA + IL-4. The enhancement of IL-12 signaling by IFN-gamma is not a direct effect of IFN-gamma on T cells, but rather is mediated by IL-12 that is produced by antigen-presenting cells in response to IFN-gamma. This positive autoregulatory effect of IL-12 on the activation of select STATs correlates with an increase in T-cell IFN-gamma production in response to IL-12. These findings suggest that the activation of STAT5 and STAT1 may augment select STAT4-dependent functional responses to IL-12 in Th1 cells.IL-17-secreting CD4(+) T cells are critically involved in inflammatory immune responses. Development of these cells is promoted in vivo and in vitro by IL-23 or TGFbeta1 plus IL-6. Despite growing interest in this inflammatory Th subset, little is known about the transcription factors that are required for their development. We demonstrate that Stat3 is required for programming the TGFbeta1 plus IL-6 and IL-23-stimulated IL-17-secreting phenotype, as well as for RORgammat expression in TGFbeta1 plus IL-6-primed cells. Moreover, retroviral transduction of a constitutively active Stat3 into differentiating T cell cultures enhances IL-17 production from these cells. We further show that Stat4 is partially required for the development of IL-23-, but not TGFbeta1 plus IL-6-primed IL-17-secreting cells, and is absolutely required for IL-17 production in response to IL-23 plus IL-18. The requirements for Stat3 and Stat4 in the development of these IL-17-secreting subsets reveal additional mechanisms in Th cell fate decisions during the generation of proinflammatory cell types.The Ca(2+) dependent transcription factor family known as nuclear factor of activated T cells (NFAT) has been shown to be important in T-cell immune responses. Because NFAT proteins have a weak DNA-binding capacity, they cooperate with other transcription factors at composite sites within the promoters of target genes. Recently, NFAT was shown to also be important for the induction of specific genetic programs that guide the differentiation and effector or regulatory activities of CD4(+) T helper subsets via the transcriptional regulation of their lineage-specific transcription factors, specifically T-bet (Th1), Gata3 (Th2), RORgammat (Th17), and Foxp3 (iTregs). In addition, the NFAT family governs the transcription of several signature cytokines, including their cytokine receptors. Subsequently, the integration of these complex intracellular signal transduction cascades is considered to critically determine the crosstalk between the T-cell receptor and receptors that are activated by both the adaptive and innate immune systems to determine pathways of T helper cell differentiation and function. Here, we carefully review the critical role of the established transcriptional partners and functional outcomes of these NFAT interactions in regard to the effector responses of these clinically relevant CD4(+) T helper subsets.Compelling evidence suggests that the transcription factor Foxp3 acts as a master switch governing the development and function of CD4(+) regulatory T cells (Tregs). However, whether transcriptional control of Foxp3 expression itself contributes to the development of a stable Treg lineage has thus far not been investigated. We here identified an evolutionarily conserved region within the foxp3 locus upstream of exon-1 possessing transcriptional activity. Bisulphite sequencing and chromatin immunoprecipitation revealed complete demethylation of CpG motifs as well as histone modifications within the conserved region in ex vivo isolated Foxp3(+)CD25(+)CD4(+) Tregs, but not in naïve CD25(-)CD4(+) T cells. Partial DNA demethylation is already found within developing Foxp3(+) thymocytes; however, Tregs induced by TGF-beta in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-beta-induced Foxp3(+) Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-beta. Our data suggest that expression of Foxp3 must be stabilized by epigenetic modification to allow the development of a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of Tregs and for the understanding of long-term cell lineage decisions.Immune homeostasis is dependent on tight control over the size of a population of regulatory T (T(reg)) cells capable of suppressing over-exuberant immune responses. The T(reg) cell subset is comprised of cells that commit to the T(reg) lineage by upregulating the transcription factor Foxp3 either in the thymus (tT(reg)) or in the periphery (iT(reg)). Considering a central role for Foxp3 in T(reg) cell differentiation and function, we proposed that conserved non-coding DNA sequence (CNS) elements at the Foxp3 locus encode information defining the size, composition and stability of the T(reg) cell population. Here we describe the function of three Foxp3 CNS elements (CNS1-3) in T(reg) cell fate determination in mice. The pioneer element CNS3, which acts to potently increase the frequency of T(reg) cells generated in the thymus and the periphery, binds c-Rel in in vitro assays. In contrast, CNS1, which contains a TGF-beta-NFAT response element, is superfluous for tT(reg) cell differentiation, but has a prominent role in iT(reg) cell generation in gut-associated lymphoid tissues. CNS2, although dispensable for Foxp3 induction, is required for Foxp3 expression in the progeny of dividing T(reg) cells. Foxp3 binds to CNS2 in a Cbf-beta-Runx1 and CpG DNA demethylation-dependent manner, suggesting that Foxp3 recruitment to this 'cellular memory module' facilitates the heritable maintenance of the active state of the Foxp3 locus and, therefore, T(reg) lineage stability. Together, our studies demonstrate that the composition, size and maintenance of the T(reg) cell population are controlled by Foxp3 CNS elements engaged in response to distinct cell-extrinsic or -intrinsic cues.The forkhead DNA-binding protein FOXP3 is critical for the development and suppressive function of CD4(+)CD25(+) regulatory T cells (T(REG)), which play a key role in maintaining self-tolerance. Functionally, FOXP3 is capable of repressing transcription of cytokine genes regulated by NFAT. Various mechanisms have been proposed by which FOXP3 mediates these effects. Using novel cell lines that inducibly express either wild-type or mutant FOXP3, we have identified NFAT2 as an early target of FOXP3-mediated transcriptional repression. NFAT2 is typically expressed at low levels in resting T cells, but is up-regulated by NFAT1 upon cellular activation. We demonstrate that transcription from the NFAT2 promoter is significantly suppressed by FOXP3, and NFAT2 protein expression is markedly diminished in activated CD4(+)CD25(+)FOXP3(+) T(REG) compared with CD4(+)CD25(-)FOXP3(-) T cells. Chromatin immunoprecipitation experiments indicate that FOXP3 competes with NFAT1 for binding to the endogenous NFAT2 promoter. This antagonism of NFAT2 activity by FOXP3 is important for the anergic phenotype of T(REG), as ectopic expression of NFAT2 from a retroviral LTR partially restores expression of IL-2 in FOXP3(+) T(REG). These data suggest that FOXP3 functions not only to suppress the first wave of NFAT-mediated transcriptional responses, but may also affect sustained NFAT-mediated inflammatory gene expression through suppression of inducible NFAT2 transcription.IL-23 is a heterodimeric cytokine composed of the IL-12p40 "soluble receptor" subunit and a novel cytokine-like subunit related to IL-12p35, termed p19. Human and mouse IL-23 exhibit some activities similar to IL-12, but differ in their capacities to stimulate particular populations of memory T cells. Like IL-12, IL-23 binds to the IL-12R subunit IL-12Rbeta1. However, it does not use IL-12Rbeta2. In this study, we identify a novel member of the hemopoietin receptor family as a subunit of the receptor for IL-23, "IL-23R." IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness on cells expressing both subunits. Human IL-23, but not IL-12, exhibits detectable affinity for human IL-23R. Anti-IL-12Rbeta1 and anti-IL-23R Abs block IL-23 responses of an NK cell line and Ba/F3 cells expressing the two receptor chains. IL-23 activates the same Jak-stat signaling molecules as IL-12: Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different DNA-binding stat complexes form in response to IL-23 compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with stat3. The ability of cells to respond to IL-23 or IL-12 correlates with expression of IL-23R or IL-12Rbeta2, respectively. The human IL-23R gene is on human chromosome 1 within 150 kb of IL-12Rbeta2.Interleukin 2 (IL-2), a cytokine linked to human autoimmune disease, limits IL-17 production. Here we found that deletion of the gene encoding the transcription factor STAT3 in T cells abrogated IL-17 production and attenuated autoimmunity associated with IL-2 deficiency. Whereas STAT3 induced IL-17 and the transcription factor RORγt and inhibited the transcription factor Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. STAT3 and STAT5 bound to multiple common sites across the locus encoding IL-17. The induction of STAT5 binding by IL-2 was associated with less binding of STAT3 at these sites and the inhibition of associated active epigenetic marks. 'Titration' of the relative activation of STAT3 and STAT5 modulated the specification of cells to the IL-17-producing helper T cell (T(H)17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine.One hallmark of human immunodeficiency virus type 1 (HIV-1) infection is the dysregulation of cytokine gene expression in T cells. Transfection of T cells with human T-cell leukemia type 1 or 2 transactivator results in the induction of the T-cell-restricted cytokine interleukin-2 (IL-2) and its receptor (IL-2Ralpha). However, no T-cell-specific factor(s) has been directly linked with the regulation of IL-2 and IL-2Ralpha transcription by influencing the promoter activity. Thymocytes from SATB1 (special AT-rich sequence binding protein 1) knockout mice have been shown to ectopically express IL-2Ralpha, suggesting involvement of SATB1 in its negative regulation. Here we show that SATB1, a T-cell-specific global gene regulator, binds to the promoters of human IL-2 and IL-2Ralpha and recruits histone deacetylase 1 (HDAC1) in vivo. SATB1 also interacts with Tat in HIV-1-infected T cells. The functional interaction between HIV-1 Tat and SATB1 requires its PDZ-like domain, and the binding of the HDAC1 corepressor occurs through the same. Furthermore, Tat competitively displaces HDAC1 that is bound to SATB1, leading to increased acetylation of the promoters in vivo. Transduction with SATB1 interaction-deficient soluble Tat (Tat 40-72) and reporter assays using a transactivation-negative mutant (C22G) of Tat unequivocally demonstrated that the displacement of HDAC1 itself is sufficient for derepression of these promoters in vivo. These results suggest a novel mechanism by which HIV-1 Tat might overcome SATB1-mediated repression in T cells.T helper type 1 (T(H)1) cell development involves interferon-gamma (IFN-gamma) signaling through signal transducer and activator of transcription 1 (STAT1) and interleukin-12 (IL-12) signaling through STAT4 activation. We examined here T-bet regulation and evaluated the actions of T-bet in STAT1- and STAT4-dependent T(H)1 development processes. We found that T-bet expression during T cell activation was strongly dependent on IFN-gamma signaling and STAT1 activation, but was independent of STAT4. Ectopic T-bet expression strongly increased IFN-gamma production in T(H)2 cells activated by PMA-ionomycin, but weakly increased IFN-gamma production in T(H)2 cells stimulated by IL-12 IL-18 or OVA peptide antigen-presenting cell stimulation. In contrast, IL-12 IL-18 induced IFN-gamma production remained STAT4-dependent despite ectopic T-bet expression. Ectopic T-bet expression selectively induced expression of IL-12Rbeta2, but not IL-18Ralpha, in wild-type and STAT1(-/-) T(H)2 cells, but did not extinguish expression of GATA-3 and T(H)2 cytokines. Finally, ectopic T-bet did not directly induce expression of endogenous T- bet independently of IFN-gamma or STAT1. Thus, T-bet is induced by IFN-gamma and STAT1 signaling during T cell activation. In addition, T-bet mediates STAT1-dependent processes of T(H)1 development, including the induction of IL-12Rbeta2.The T cell molecule CD28 provides a co-stimulatory signal that is required for T cell proliferation, and has been implicated in the control of T cell anergy. An important clue to the signaling mechanism of CD28 is the finding that CD28 can bind to phosphatidylinositol 3-kinase (PI 3-kinase) by means of a cytoplasmic phospho-YMNM (pYMNM) motif. A remaining issue concerns whether CD28 can recruit other intracellular signaling molecules. In this study, we show that CD28 uses the same pYMNM motif to recruit a second intracellular protein, GRB-2. CD28-associated GRB-2, as detected by anti-GRB-2 immunoblotting, was found in human peripheral T cells, HPB-ALL and Jurkat cells. As in the case of PI3-kinase, antibody-induced cross-linking of CD28 induces a time-dependent recruitment of GRB-2. Likewise, mutation of the pY-191 residue within the pYMNM motif reduces GRB-2 binding. Peptide binding studies show that the SH2 domain of GRB-2 binds to the pYMNM motif with an affinity comparable to GRB-2/SHC, but some 10- to 100-fold lower than the CD28/PI 3-kinase. Despite this, CD28/GRB-2 and CD28/PI 3-kinase complexes are found to co-exist in peripheral T cells. Finally, immunoblotting shows that CD28 also associates with the gene product of the human homolog of the Drosophila Son of sevenless gene (SOS), a GRB-2-complexed guanine nucleotide exchange factor responsible for converting p21ras to a GTP-bound active state. CD28-associated GRB2/SOS is likely to serve an important link in the regulation of p21ras and lymphokine expression mediated by CD28.The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are activated by environmental stress. JNK is also activated by proinflammatory cytokines, such as TNF and IL-1, and Toll-like receptor ligands. This pathway, therefore, can act as a critical convergence point in immune system signaling for both adaptive and innate responses. Like other MAPKs, the JNKs are activated via the sequential activation of protein kinases that includes two dual-specificity MAP kinase kinases (MKK4 and MKK7) and multiple MAP kinase kinase kinases. MAPKs, including JNKs, can be deactivated by a specialized group of phosphatases, called MAP kinase phosphatases. JNK phosphorylates and regulates the activity of transcription factors other than c-Jun, including ATF2, Elk-1, p53 and c-Myc and non-transcription factors, such as members of the Bcl-2 family. The pathway plays a critical role in cell proliferation, apoptosis, angiogenesis and migration. In this review, an overview of the functions that are related to rheumatic diseases is presented. In addition, some diseases in which JNK participates will be highlighted.NFAT transcription factors play critical roles in gene transcription during immune responses. To investigate further the two most prominent NFAT family members, NFATc1 and NFATc2, we generated mice bearing lymphoid systems devoid of both. Doubly deficient T cells displayed cell surface markers of activation yet were significantly deficient in the development of multiple effector functions, including Th cytokine production, surface effector molecule expression, and cytolytic activity. Nevertheless, doubly deficient B cells were hyperactivated, as evidenced by extremely elevated serum IgG1 and IgE, as well as plasma cell expansion and infiltration of end organs. Thus, in T cells, NFATc1 and NFATc2 are dispensable for inflammatory reactivity but are required for effector differentiation, while in B cells, NFATs regulate both normal homeostasis and differentiation.Host immune responses are finely regulated by the opposing effects of Th17 and T regulatory (Treg) cells. Treg cells help to dampen inflammatory processes and Th17 cells facilitate various aspects of immune activation. The differentiation of Th cells depends on a unique combination of stimulants and subsequent activation of diverse transcription factors. In particular, cooperative activation of NFAT and Smad3 leads to the induction of Treg cells, and cooperation among STAT3 and Smad3 switches to the induction of Th17 cells. We have previously shown that the IL-1 receptor associated kinase 1 (IRAK-1) selectively activates STAT3 and inactivates NFAT. Physiological studies have shown that IRAK-1(-/-) mice are protected from developing various inflammatory diseases, including experimental autoimmune encephalomyelitis and atherosclerosis with unknown mechanism. In this study, we demonstrate that IRAK-1 plays a critical modulatory role in the differentiation of Th17 and Treg cells. Following stimulation with TCR agonists and TGFbeta, IRAK-1(-/-) CD4 Th cells display elevated nuclear NFATc2 levels and increased interaction of NFATc2 and Smad3, resulting in increased expression of Foxp3, a key marker for Treg cells. IRAK-1(-/-) mice have constitutively higher populations of Treg cells. In contrast, when stimulated with TCR agonists together with IL-6 and TGF-beta, IRAK-1(-/-) CD4 Th cells exhibit attenuated STAT3 Ser727 phosphorylation and reduced expression of IL-17 and RORgamma t compared with wild-type cells. Correspondingly, IRAK-1 deletion results in decreased IL-17 expression and dampened inflammatory responses in acute and chronic inflammatory mice models. Our data provides mechanistic explanation for the anti-inflammatory phenotypes of IRAK-1(-/-) mice.The transcription factor Foxp3 is involved in the differentiation, function and survival of CD4+CD25+ regulatory T (T(reg)) cells. Details of the mechanism underlying the induction of Foxp3 expression remain unknown, because studies of the transcriptional regulation of the Foxp3 gene are limited by the small number of T(reg) cells in mononuclear cell populations. Here we have generated a model system for analyzing Foxp3 induction and, by using this system with primary T cells, we have identified an enhancer element in this gene. The transcription factors Smad3 and NFAT are required for activity of this Foxp3 enhancer, and both factors are essential for histone acetylation in the enhancer region and induction of Foxp3. These biochemical properties that define Foxp3 expression explain many of the effects of transforming growth factor-beta on the function of Foxp3+ T(reg) cells.Transforming growth factor beta (TGF-beta) is a crucial cytokine with pleiotropic functions on immune cells. In CD4(+) T cells, TGF-beta is required for induction of both regulatory T and Th17 cells. However, the molecular mechanism underlying this differential T cell fate decision remains unclear. In this study, we have evaluated the role of Smad3 in the development of Th17 and regulatory T cells. Smad3 was found to be dispensable for natural regulatory T cell function. However, induction of Foxp3 expression by TGF-beta in naive T cells was significantly reduced in the absence of this molecule. On the contrary, Smad3 deficiency led to enhanced Th17 differentiation in vitro and in vivo. Moreover, Smad3 was found to interact with retinoid acid receptor-related orphan receptor gammat (RORgammat) and decrease its transcriptional activity. These results demonstrate that Smad3 is differentially involved in the reciprocal regulatory and inflammatory T cell generation.Overactive responses by interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) are tightly linked to the development of autoimmunity, yet the factors that negatively regulate the differentiation of this lineage remain unknown. Here we report that the transcription factor T-bet suppressed development of the T(H)17 cell lineage by inhibiting transcription of Rorc (which encodes the transcription factor RORγt). T-bet interacted with the transcription factor Runx1, and this interaction blocked Runx1-mediated transactivation of Rorc. T-bet Tyr304 was required for formation of the T-bet-Runx1 complex, for blockade of Runx1 activity and for inhibition of the T(H)17 differentiation program. Our data reinforce the idea of master regulators that shape immune responses by simultaneously activating one genetic program while silencing the activity of competing regulators in a common progenitor cell.Although prolactin and interleukin 2 (IL-2) can elicit distinct physiological responses, we have found that their signal pathways share a common signal transducer and activator of transcription, STAT5. STAT5 was originally identified as a mammary gland factor induced by prolactin in lactating breast cells. Here we demonstrate that STAT5 is activated after IL-2 stimulation of two responsive lymphocyte cell lines, Nb2 and YT. Activation of STAT5 is measured both by IL-2-induced tyrosine phosphorylation and by IL-2-induced DNA binding. The STAT5 DNA recognition site is the same as the interferon gamma-activated site (GAS) in the interferon regulatory factor 1 gene. We demonstrate that the GAS element is necessary and sufficient for transcriptional induction by both IL-2 and prolactin in T lymphocytes. These results indicate that the role of STAT5 in the regulation of gene expression is not restricted to mammary cells or to prolactin, but is an integral part of the signal pathway of a critical immunomodulatory cytokine, IL-2.Since CD28 provides cosignals in T cell responses, a key question is whether the coreceptor operates exclusively via TCRzeta/CD3 or also operates as an independent signaling unit. In this study, we show that CD28 can cooperate with VAV/SLP-76 adaptors to upregulate interleukin 2/4 transcription independently of TCR ligation. CD28 signaling is dependent on VAV/SLP-76 complex formation and induces membrane localization of these complexes. CD28-VAV/SLP-76 also functions in nonlymphoid cells to promote nuclear entry of NFAT, indicating that these adaptors are the only lymphoid components needed for this pathway. Further downstream, CD28-VAV/SLP-76 synergizes with Rac1 and causes F-actin remodelling proximal to receptor. Autonomous CD28 signaling may account for the distinct nature of the second signal and in trans amplification of T cell responses.T-bet and GATA3 regulate the CD4+ T cell Th1/Th2 cell fate decision but little is known about the interplay between these factors outside of the murine Ifng and Il4/Il5/Il13 loci. Here we show that T-bet and GATA3 bind to multiple distal sites at immune regulatory genes in human effector T cells. These sites display markers of functional elements, act as enhancers in reporter assays and are associated with a requirement for T-bet and GATA3. Furthermore, we demonstrate that both factors bind distal sites at Tbx21 and that T-bet directly activates its own expression. We also show that in Th1 cells, GATA3 is distributed away from Th2 genes, instead occupying T-bet binding sites at Th1 genes, and that T-bet is sufficient to induce GATA3 binding at these sites. We propose these aspects of T-bet and GATA3 function are important for Th1/Th2 differentiation and for understanding transcription factor interactions in other T cell lineage decisions.The TCR can detect subtle differences in the strength of interaction with peptide/MHC ligand and transmit this information to influence downstream events in T cell responses. Manipulation of the factor commonly referred to as TCR signal strength can be achieved by changing the amount or quality of peptide/MHC ligand. Recent work has enhanced our understanding of the many variables that contribute to the apparent cumulative strength of TCR stimulation during immunogenic and tolerogenic T cell responses. In this review, we consider data from in vitro studies in the context of in vivo immune responses and discuss in vivo consequences of manipulation of strength of TCR stimulation, including influences on T cell-APC interactions, the magnitude and quality of the T cell response, and the types of fate decisions made by peripheral T cells.Forkhead box P3 (FOXP3) is considered a specific marker for CD4(+)CD25(+) regulatory T (Treg) cells, but increasing evidence suggests that human CD4(+)CD25(-) effector T (Teff) cells can transiently express FOXP3 upon activation. We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cells. In contrast, cytokines which do not activate STAT5, such as IL-4 or transforming growth factor-beta alone, do not directly induce FOXP3 expression in activated Teff cells. Moreover, expression of a constitutively active form of STAT5a is sufficient to induce FOXP3 expression in Teff cells. Expression of FOXP3 in activated Teff cells requires both TCR-mediated activation and endogenous IL-2, but is not dependent on cell division and does not induce suppressive function. The presence of STAT5-activating cytokines is also required to maintain high FOXP3 expression and suppressive activity of Treg cells in vitro. These data indicate that activation of STAT5 sustains FOXP3 expression in both Treg and Teff cells and contribute to our understanding of how cytokines affect the expression of FOXP3.The relative activity of regulatory versus conventional CD4(+) T cells ultimately maintains the delicate balance between immune tolerance and inflammation. At the molecular level, the activity of phosphatidylinositol 3-kinase (PI3K) and its downstream positive and negative regulators has a major role in controlling the balance between immune regulation and activation of different subsets of effector CD4(+) T cells. In contrast to effector T cells which require activation of the PI3K to differentiate and mediate their effector function, regulatory T cells rely on minimal activation of this pathway to develop and maintain their characteristic phenotype, function, and metabolic state. In this review, we discuss the role of the PI3K signaling pathway in CD4(+) T cell differentiation and function, and focus on how modulation of this pathway in T cells can alter the outcome of an immune response, ultimately tipping the balance between tolerance and inflammation.CD4(+)FOXP3(+) regulatory T (Treg) cells are essential for maintaining immunological self-tolerance. Treg cell development and function depend on the transcription factor FOXP3, which is present in several distinct isoforms due to alternative splicing. Despite the importance of FOXP3 in the proper maintenance of Treg cells, the regulation and functional consequences of FOXP3 isoform expression remains poorly understood. Here, we show that in human Treg cells IL-1β promotes excision of FOXP3 exon 7. FOXP3 is not only expressed by Treg cells but is also transiently expressed when naïve T cells differentiate into Th17 cells. Forced splicing of FOXP3 into FOXP3Δ2Δ7 strongly favored Th17 differentiation in vitro. We also found that patients with Crohn's disease express increased levels of FOXP3 transcripts lacking exon 7, which correlate with disease severity and IL-17 production. Our results demonstrate that alternative splicing of FOXP3 modulates T cell differentiation. These results highlight the importance of characterizing FOXP3 expression on an isoform basis and suggest that immune responses may be manipulated by modulating the expression of FOXP3 isoforms, which has broad implications for the treatment of autoimmune diseases.IL-17-producing T helper cells (Th17) have been recently identified as a previously undescribed subset of helper T cells. Here, we demonstrate that aryl hydrocarbon receptor (Ahr) has an important regulatory function in the commitment of Th17 cells. Ahr was robustly induced under Th17-polarizing conditions. Ahr-deficient naïve T cells showed a considerable loss in the ability to differentiate into Th17 cells when induced by TGF-beta plus IL-6. We were able to demonstrate that Ahr interacts with Stat1 and Stat5, which negatively regulate Th17 development. Whereas Stat1 activation returned to its basal level in Ahr wild type naïve T cells 24 h after stimulation with TGF-beta plus IL-6, Stat1 remained activated in Ahr-deficient naïve T cells after stimulation. These results indicate that Ahr participates in Th17 cell differentiation through regulating Stat1 activation, a finding that constitutes additional mechanisms in the modulation of Th17 cell development.Activation of PI3K is among the earliest signaling events observed in T cells after conjugate formation with antigen-presenting cells (APCs). The relevant PI3K catalytic isoform and relative contribution of the TcR and CD28 to PI3K activity at the immune synapse have not been determined unequivocally. Using a quantitative imaging-based assay, we show that the PI3K activity at the T cell-APC contact area is dependent on the p110delta, but not the p110gamma, isoform of PI3K. CD28 enhanced PIP3 production at the T-cell synapse independently of its YMNM PI3K-recruitment motif that instead was required for efficient PKC recruitment. CD28 could partially compensate for the lack of p110delta activity during T-cell activation, which indicates that CD28 and p110delta act in parallel and complementary pathways to activate T cells. Consistent with this, CD28 and p110delta double-deficient mice were severely immune compromised. We therefore suggest that combined pharmaceutic targeting of p110delta activity and CD28 costimulation has potent therapeutic potential.The CARD domain protein BCL10 and paracaspase MALT1 are essential for the activation of IkappaB kinase (IKK) and NF-kappaB in response to T cell receptor (TCR) stimulation. Here we present evidence that TRAF6 ubiquitin ligase and TAK1 protein kinase mediate IKK activation by BCL10 and MALT1. RNAi-mediated silencing of MALT1, TAK1, TRAF6, and TRAF2 suppressed TCR-dependent IKK activation and interleukin-2 production in T cells. Furthermore, we have reconstituted the pathway from BCL10 to IKK activation in vitro with purified proteins of MALT1, TRAF6, TAK1, and ubiquitination enzymes including Ubc13/Uev1A. We find that a small fraction of BCL10 and MALT1 proteins form high molecular weight oligomers. Strikingly, only these oligomeric forms of BCL10 and MALT1 can activate IKK in vitro. The MALT1 oligomers bind to TRAF6, induce TRAF6 oligomerization, and activate the ligase activity of TRAF6 to polyubiquitinate NEMO. These results reveal an oligomerization --> ubiquitination --> phosphorylation cascade that culminates in NF-kappaB activation in T lymphocytes.Since the discovery of the first nuclear factor of activated T cells (NFAT) protein more than a decade ago, the NFAT family of transcription factors has grown to include five members. It has also become clear that NFAT proteins have crucial roles in the development and function of the immune system. In T cells, NFAT proteins not only regulate activation but also are involved in the control of thymocyte development, T-cell differentiation and self-tolerance. The functional versatility of NFAT proteins can be explained by their complex mechanism of regulation and their ability to integrate calcium signalling with other signalling pathways. This Review focuses on the recent advances in our understanding of the regulation, mechanism of action and functions of NFAT proteins in T cells.Members of the phosphoinositide-3 kinase (PI3K) family control several cellular responses including cell growth, survival, cytoskeletal remodeling and the trafficking of intracellular organelles in many different types of cell. In particular PI3K has important functions in the immune system. It has been difficult to evaluate the roles of distinct PI3Ks in cellular immune responses because no PI3K inhibitors are specific for individual family members and because most stimuli activate several PI3K enzymes. The development of gene-targeted mice now enables us to examine the physiological functions of individual PI3K enzymes in the immune system in vivo.The transcription factor GATA3 is crucial for the differentiation of naive CD4(+) T cells into T helper 2 (Th2) cells. Here, we show that deletion of Gata3 allowed the appearance of interferon-gamma (IFN-gamma)-producing cells in the absence of interleukin-12 (IL-12) and IFN-gamma. Such IFN-gamma production was transcription factor T-bet independent. Another T-box-containing transcription factor Eomes, but not T-bet, was induced both in GATA3-deficient CD4(+) T cells differentiated under Th2 cell conditions and in Th2 cells with enforced Runx3 expression, contributing to IFN-gamma production. GATA3 overexpression blocked Runx3-mediated Eomes induction and IFN-gamma production, and GATA3 protein physically interacted with Runx3 protein. Furthermore, we found that Runx3 directly bound to multiple regulatory elements of the Ifng gene and that blocking Runx3 function in either Th1 or GATA3-deficient "Th2" cells results in diminished IFN-gamma production by these cells. Thus, the Runx3-mediated pathway, actively suppressed by GATA3, induces IFN-gamma production in a STAT4- and T-bet-independent manner.Scurfy mice, which are deficient in a functional Foxp3, exhibit a severe lymphoproliferative disorder and display generalized over-production of cytokines. Here, we show that, among the Foxp transcriptional factor family, which includes Foxp1, Foxp2, and Foxp3, only Foxp3 has the ability to inhibit IL-2, IL-4, and IFN-gamma production by primary T helper cells. We found that Foxp3 physically associates with the Rel family transcription factors, nuclear factor of activated T cells (NFAT) and NF-kappaB, and blocks their ability to induce the endogenous expression of their target genes, including key cytokine genes. More importantly, T cells derived from scurfy mice have a dramatic increase in nuclear factor of activated T cells (NFAT) and NF-kappa B transcriptional activity compared with the T cells derived from WT mice. Furthermore, complementation of Foxp3 in scurfy-derived T cells lowers the NFAT and NF-kappa B transcriptional activity to the physiological level. Finally, we show that myelin proteolipid protein-specific autoreactive T cells transduced with Foxp3 cannot mediate experimental autoimmune encephalomyelitis, providing further support that Foxp3 suppresses the effector function of autoreactive T cells. Foxp3 has already been associated with the generation of CD4(+)CD25+ regulatory T cells; our data additionally demonstrate that Foxp3 suppresses the effector functions of T helper cells by directly inhibiting the activity of two key transcription factors, NFAT and NF-kappa B, which are essential for cytokine gene expression and T cell functions.Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper type 2 cells. Here we show that IRF4 is also critical for the generation of interleukin 17-producing T helper cells (T(H)-17 cells), which are associated with experimental autoimmune encephalomyelitis. IRF4-deficient (Irf4(-/-)) mice did not develop experimental autoimmune encephalomyelitis, and T helper cells from such mice failed to differentiate into T(H)-17 cells. Transfer of wild-type T helper cells into Irf4(-/-) mice rendered the mice susceptible to experimental autoimmune encephalomyelitis. Irf4(-/-) T helper cells had less expression of RORgammat and more expression of Foxp3, transcription factors important for the differentiation of T(H)-17 and regulatory T cells, respectively. Altered regulation of both transcription factors contributed to the phenotype of Irf4(-/-) T helper cells. Our data position IRF4 at the center of T helper cell development, influencing not only T helper type 2 but also T(H)-17 differentiation.Recent work has identified a new subset of CD4(+) T cells named as Tfh cells that are localized in germinal centers and critical in germinal center formation. Tfh cell differentiation is regulated by IL-6 and IL-21, possibly via STAT3 factor, and B cell lymphoma 6 (Bcl6) is specifically expressed in Tfh cells and required for their lineage specification. In the current study, we characterized the role of STAT5 in Tfh cell development. We found that a constitutively active form of STAT5 effectively inhibited Tfh differentiation by suppressing the expression of Tfh-associated factors (CXC motif) receptor 5 (CXCR5), musculoaponeurotic fibrosarcoma (c-Maf), Bcl6, basic leucine zipper transcription factor ATF-like (Batf), and IL-21, and STAT5 deficiency greatly enhanced Tfh gene expression. Importantly, STAT5 regulated the expression of Tfh cell suppressor factor B lymphocyte-induced maturation protein 1 (Blimp-1); STAT5 deficiency impaired Blimp-1 expression and resulted in elevated expression of Tfh-specific genes. Similarly, inhibition of IL-2 potentiated Tfh generation, associated with dampened Blimp-1 expression; Blimp-1 overexpression inhibited Tfh gene expression in Stat5-deficient T cells, suggesting that the IL-2/STAT5 axis functions to regulate Blimp-1 expression. In vivo, deletion of STAT5 in CD4(+) T cells resulted in enhanced development of Tfh cells and germinal center B cells and led to an impairment of B cell tolerance in a well defined mouse tolerance model. Taken together, this study demonstrates that STAT5 controls Tfh differentiation.Transcription factors of the nuclear factor of activated T cells (NFAT) family are thought to regulate the expression of a variety of inducible genes such as interleukin-2 (IL-2), IL-4, and tumor necrosis factor-alpha. However, it remains unresolved whether NFAT proteins play a role in regulating transcription of the interferon- gamma (IFN-gamma) gene. Here it is shown that the transcription factor NFAT1 (NFATc2) is a major regulator of IFN-gamma production in vivo. Compared with T cells expressing NFAT1, T cells lacking NFAT1 display a substantial IL-4-independent defect in expression of IFN-gamma mRNA and protein. Reduced IFN-gamma production by NFAT1(-/-)x IL-4(-/-) T cells is observed after primary in vitro stimulation of naive CD4+ T cells, is conserved through at least 2 rounds of T-helper cell differentiation, and occurs by a cell-intrinsic mechanism that does not depend on overexpression of the Th2-specific factors GATA-3 and c-Maf. Concomitantly, NFAT1(-/-)x IL-4(-/-) mice show increased susceptibility to infection with the intracellular parasite Leishmania major. Moreover, IFN-gamma production in a murine T-cell clone is sensitive to the selective peptide inhibitor of NFAT, VIVIT. These results suggest that IFN-gamma production by T cells is regulated by NFAT1, most likely at the level of gene transcription.IL-1 is a proinflammatory cytokine that signals through a receptor complex of two different transmembrane chains to generate multiple cellular responses, including activation of the transcription factor NF-kappaB. Here we show that MyD88, a previously described protein of unknown function, is recruited to the IL-1 receptor complex following IL-1 stimulation. MyD88 binds to both IRAK (IL-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of IRAK with the receptor. Ectopic expression of MyD88 or its death domain-containing N-terminus activates NF-kappaB. The C-terminus of MyD88 interacts with the IL-1 receptor and blocks NF-kappaB activation induced by IL-1, but not by TNF. Thus, MyD88 plays the same role in IL-1 signaling as TRADD and Tube do in TNF and Toll pathways, respectively: it couples a serine/threonine protein kinase to the receptor complex.B lymphocyte-induced maturation protein-1 (Blimp-1), discovered 16 years ago as a transcriptional repressor of the IFNbeta promoter, plays fundamentally important roles in many cell lineages and in early development. This review focuses on Blimp-1 in lymphocytes. In the B cell lineage, Blimp-1 is required for development of immunoglobulin-secreting cells and for maintenance of long-lived plasma cells (LLPCs). Direct targets of Blimp-1 and the transcriptional cascades Blimp-1 initiates to trigger plasmacytic differentiation are described. Blimp-1 also affects the homeostasis and function of CD4(+), CD8(+), and regulatory CD4(+) T cells, and Blimp-1 levels are highest in antigen-experienced T cells. Blimp-1 attenuates T cell proliferation and survival and modulates differentiation. Roles for Blimp-1 in Th1/Th2 specification, regulatory T cell function, and CD8 differentiation and function are under investigation. Signals that induce Blimp-1 in B cells include Toll-like receptor ligands and cytokines; in T cells, T cell receptors and cytokines induce Blimp-1. In spite of some commonalities, different targets and regulators of Blimp-1 in B and T cells suggest intriguing evolutionary divergence of this regulatory machinery.Transforming growth factor β-activated kinase 1 (TAK1) is a key regulator of the innate immunity and the proinflammatory signaling pathway. In response to interleukin-1, tumor necrosis factor-α, and toll-like receptor agonists, it mediates the activation of the nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), and p38 pathways. In addition, TAK1 plays a central role in adaptive immunity, in which it mediates signaling from T- and B-cell receptors. This review will focus on recent developments and also examine the regulation of TAK1 in response to a diverse range of other stimuli including DNA damage, transforming growth factor-β, Wnt, osmotic stress, and hypoxia.Although protein kinase C-θ (PKC-θ)-deficient mice are resistant to the induction of Th17-dependent experimental autoimmune encephalomyelitis, the function of PKC-θ in Th17 differentiation remains unknown. In this article, we show that purified, naive CD4 PKC-θ(-/-) T cells were defective in Th17 differentiation, whereas Th1 and Th2 differentiation appeared normal. Activation of PKC-θ with PMA promoted Th17 differentiation in wild type (WT) but not PKC-θ(-/-) T cells. Furthermore, PKC-θ(-/-) T cells had notably lower levels of Stat3, a transcription factor required for Th17 differentiation, and PMA markedly stimulated the expression of Stat3 in WT but not PKC-θ(-/-) T cells. In contrast, activation of Stat4 and Stat6, which are critical for Th1 and Th2 differentiation, was normal in PKC-θ(-/-) T cells. Forced expression of Stat3 significantly increased Th17 differentiation in PKC-θ(-/-) T cells, suggesting that reduced Stat3 levels were responsible for impaired Th17 differentiation, and that Stat3 lies downstream of PKC-θ. Constitutively active PKC-θ, or WT PKC-θ activated by either PMA or TCR cross-linking, stimulated expression of a luciferase reporter gene driven by the Stat3 promoter. PKC-θ-mediated activation of the Stat3 promoter was inhibited by dominant-negative AP-1 and IκB kinase-β, but stimulated by WT AP-1 and IκB kinase-β, suggesting that PKC-θ stimulates Stat3 transcription via the AP-1 and NF-κB pathways. Lastly, conditions favoring Th17 differentiation induced the highest activation level of PKC-θ. Altogether, the data indicate that PKC-θ integrates the signals from TCR signaling and Th17 priming cytokines to upregulate Stat3 via NF-κB and AP-1, resulting in the stimulation of Th17 differentiation.Despite their importance, the molecular circuits that control the differentiation of naive T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based perturbation tools to systematically derive and experimentally validate a model of the dynamic regulatory network that controls the differentiation of mouse TH17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases. The TH17 transcriptional network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, the coupled action of which may be essential for maintaining the balance between TH17 and other CD4(+) T-cell subsets. Our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles; it also highlights novel drug targets for controlling TH17 cell differentiation.The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the toxicity of dioxins, polycyclic aromatic hydrocarbons and related environmental pollutants. Besides drug metabolism, several studies have provided evidence that the AHR and its downstream targets trigger important developmental, physiological and pathophysiological processes. However, in contrast to the molecular mechanisms of AHR-dependent signaling pathways, the transcriptional regulation of the AHR gene itself is as yet only marginally understood. We found that the pleiotropic interleukin (IL)-6-type cytokine oncostatin M (OSM) is an inducer of AHR mRNA and protein expression in human HepG2 hepatocarcinoma cells. Analyses of the human AHR promoter revealed the existence of a putative signal transducer and activator of transcription (STAT)-binding element 5'-upstream of the transcription start site. By means of site-directed mutagenesis, inhibitor experiments and electrophoretic mobility shift assays, we demonstrated that this STAT motif is recognized by STAT3 to regulate basal and cytokine-inducible AHR expression in HepG2 cells. The identification of the AHR as a downstream target of IL-6-type cytokine-stimulated STAT3 signaling may contribute to a better understanding of the multiple facets of AHR during development, physiology and disease.Here we describe a novel role for the phosphatidylinositol 3-kinase/AKT pathway in mediating induction of interleukin-6 (IL-6) in response to IL-1. Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited IL-6 mRNA and protein production. Overexpression of either dominant-negative AKT or IkappaB kinase alpha mutant, IKKalphaT23A, containing a mutation in a functional AKT phosphorylation site, shown previously to be important for NFkappaB activation, completely abrogated IL-6 promoter activation in response to IL-1. However, mutation of the consensus NFkappaB site on the IL-6 promoter did not abrogate promoter activation by IL-1 in contrast to the AP-1 site mutation. IL-1 induces phosphorylation of IKKalpha on the NFkappaB inducing kinase (NIK) phosphorylation sites Ser(176)/Ser(180) and on the Thr(23) site, and although phosphorylation of IKKalphaT23 is inhibited both by LY294002 and wortmannin, phosphorylation of Ser(176)/Ser(180) is not. Neither inhibition of PI 3-kinase/AKT nor IKKalphaT23A overexpression affected IkappaBalpha degradation in response to IL-1. Only partial inhibition by dominant-negative AKT and no inhibitory effect of IKKalphaT23A was observed on an IL-6 promoter-specific NFkappaB site in contrast to significant inhibitory effects on the AP-1 site. Taken together, we have discovered a novel PI 3-kinase/AKT-dependent pathway in response to IL-1, encompassing PI 3-kinase/AKT/IKKalphaT23 upstream of AP-1. This novel pathway is a parallel pathway to the PI 3-kinase/AKT upstream of NFkappaB and both are involved in IL-6 gene transcription in response to IL-1.Protein kinase C theta (PKCtheta) is a member of the novel, Ca(2+)-independent PKC subfamily, which plays an important and non-redundant role in several aspects of T cell biology. Much progress has been accomplished in understanding the function of PKCtheta in the immune system and its unique translocation to the immunological synapse in Ag-stimulated T lymphocytes. Biochemical and genetic approaches revealed that PKCtheta is required for the activation of mature T cells as well as for their survival. Mutation of the PKCtheta gene leads to impaired receptor-induced stimulation of the transcription factors AP-1, NF-kappaB and NFAT, which results in defective T cell activation, and to aberrant expression of apoptosis-related proteins, resulting in poor T cell survival. Furthermore, PKCtheta-deficient mice display defects in the differentiation of T helper subsets, particularly in Th2- and Th17-mediated inflammatory responses. Therefore, PKCtheta is a critical enzyme that regulates T cell function at multiple stages, and it represents an attractive drug target for allergic and autoimmune diseases.Regulatory T cell (Treg) activity is modulated by a cooperative complex between the transcription factor NFAT and FOXP3, a lineage specification factor for Tregs. FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs. However, FOXP3 is expressed transiently in conventional CD4(+) T cells upon TCR stimulation and may lead to T cell hyporesponsiveness. We found that a short synthetic peptide able to inhibit FOXP3/NFAT interaction impaired suppressor activity of conventional Tregs in vitro. Specific inhibition of FOXP3/NFAT interaction with this inhibitory peptide revealed that FOXP3 downregulates NFAT-driven promoter activity of CD40L and IL-17. Inhibition of FOXP3/NFAT interaction upregulated CD40L expression on effector T cells and enhanced T cell proliferation and IL-2, IFN-γ, IL-6, or IL-17 production in response to TCR stimulation. The inhibitory peptide impaired effector T cell conversion into induced Tregs in the presence of TGF-β. Moreover, in vivo peptide administration showed antitumor efficacy in mice bearing Hepa129 or TC1 tumor cells when combined with sorafenib or with an antitumor vaccine, respectively. Our results suggest that inhibition of NFAT/FOXP3 interaction might improve antitumor immunotherapies.Interleukin (IL)-2 is the predominant cytokine that is produced by naive Th cells in a primary response. It is required for proliferation and differentiation of Th precursor cells into effector cells. Initial high-level IL-2 production is followed by its decline, and the concomitant induction of cytokines that are typical of the differentiated state. Although the factors that are responsible for the early induction of IL-2 are well defined, the mechanisms that are responsible for its down-regulation in later stages of Th development have not been studied as much. Previous work from our laboratory revealed a repressor function for the T-box transcription factor, T-bet, in IL-2 gene transcription. Here, we report that T-bet(S508) is required for the optimal repression of IL-2 production in developing Th1 cells. Phosphorylation of T-bet(S508) by casein kinase I and glycogen synthase kinase-3 kinases accompanies T-bet's interaction with the RelA nuclear factor-kappaB transcription factor. Heterodimerization of T-bet and RelA interferes with the binding of RelA to the IL-2 promoter, and hence, transcriptional activation of the IL-2 gene by RelA.T helper 17 (Th17) cells play major roles in autoimmunity and bacterial infections, yet how T cell receptor (TCR) signaling affects Th17 cell differentiation is relatively unknown. We demonstrate that CD4(+) T cells lacking Itk, a tyrosine kinase required for full TCR-induced phospholipase C-gamma (PLC-gamma1) activation, exhibit decreased interleukin-17A (IL-17A) expression in vitro and in vivo, despite relatively normal expression of retinoic acid receptor-related orphan receptor-gammaT (ROR-gammaT) and IL-17F. IL-17A expression was rescued by pharmacologically induced Ca(2+) influx or constitutively activated nuclear factor of activated T cells (NFAT). Conversely, decreased TCR stimulation or calcineurin inhibition preferentially reduced IL-17A expression. We further found that the promoter of Il17a but not Il17f has a conserved NFAT binding site that bound NFATc1 in wild-type but not Itk-deficient cells, even though both exhibited open chromatin conformations. Finally, Itk(-/-) mice also showed differential regulation of IL-17A and IL-17F in vivo. Our results suggest that Itk specifically couples TCR signaling to Il17a expression and the differential regulation of Th17 cell cytokines through NFATc1.Th1 and Th17 cells are crucial in immune regulation and autoimmune disease development. By adding Stat6 deficiency to T-bet deficiency, and thus negating effects from elevated levels of IL-4/Stat6/GATA3 Th2 signals in T-bet-deficient cells, we investigated the signals important for Th1 and Th17 cell differentiation and their role in colitis development. The data reveal that Eomesodermin compensates T-bet deficiency for IFN-gamma and Th1 development. However, without T-bet, IFN-gamma production and Th1 differentiation are susceptible to inhibition by IL-6 and TGFbeta. As a result, Th17 development is strongly favored, the threshold for TGFbeta requirement is lowered, and IL-6 drives Th17 differentiation, elucidating a critical role for T-bet in directing T cell differentiation to Th1 vs Th17. In contrast to IL-6 plus TGFbeta-driven Th17, IL-6-driven Th17 cells do not express IL-10 and they induce a more intense colitis. Naive CD4 T cells deficient in Stat6 and T-bet also induce a Th17-dominant colitis development in vivo. Our data provide new insights into the choice between Th1 and Th17 development and their roles in autoimmunity.IL-12 and IL-18 synergistically enhance IFN-gamma mRNA transcription by activating STAT4 and AP-1, respectively. However, it is still unknown how STAT4/AP-1 elicit IFN-gamma promoter activation. Using an IL-12/IL-18-responsive T cell clone, we investigated the mechanisms underlying synergistic enhancement of IFN-gamma mRNA expression induced by these two cytokines. Synergy was observed in a reporter gene assay using an IFN-gamma promoter fragment that binds AP-1, but not STAT4. An increase in c-Jun, a component of AP-1, in the nuclear compartment was elicited by stimulation with either IL-12 or IL-18, but accumulation of serine-phosphorylated c-Jun was induced only by IL-18 capable of activating c-Jun N-terminal kinase. The binding of AP-1 to the relevant promoter sequence depended on the presence of STAT4. STAT4 bound with c-Jun, and a phosphorylated c-Jun-STAT4 complex most efficiently interacted with the AP-1-relevant promoter sequence. Enhanced cobinding of STAT4 and c-Jun to the AP-1 sequence was also observed when activated lymph node T cells were exposed to IL-12 plus IL-18. These results show that STAT4 up-regulates AP-1-mediated IFN-gamma promoter activation without directly binding to the promoter sequence, providing a mechanistic explanation for IL-12/IL-18-induced synergistic enhancement of IFN-gamma gene expression.One of the major goals in immunology research is to understand the regulatory mechanisms that underpin the rapid switch on/off of robust and efficient effector (Teffs) or regulatory (Tregs) T-cell responses. Understanding the molecular mechanisms underlying the regulation of such responses is critical for the development of effective therapies. T-cell activation involves the engagement of T-cell receptor and co-stimulatory signals, but the subsequent recruitment of serine/threonine-specific protein Kinase C-theta (PKC-θ) to the immunological synapse (IS) is instrumental for the formation of signaling complexes, which ultimately lead to a transcriptional network in T cells. Recent studies demonstrated that major differences between Teffs and Tregs occurred at the IS where its formation induces altered signaling pathways in Tregs. These pathways are characterized by reduced recruitment of PKC-θ, suggesting that PKC-θ inhibits Tregs suppressive function in a negative feedback loop. As the balance of Teffs and Tregs has been shown to be central in several diseases, it was not surprising that some studies revealed that PKC-θ plays a major role in the regulation of this balance. This review will examine recent knowledge on the role of PKC-θ in T-cell transcriptional responses and how this protein can impact on the function of both Tregs and Teffs.Naive CD4(+) T cells undergo massive proliferation and differentiation into at least four distinct helper T cell subsets after recognition of foreign antigen-derived peptides presented by dendritic cells. Each helper T cell subset expresses a distinct set of genes that encode unique transcription factor(s), as well as hallmark cytokines. The cytokine environment created by activated CD4(+) T cells, dendritic cells and/or other cell types during the course of differentiation is a major determinant for the helper T cell fate. This Review focuses on the role of cytokines of the common γ-chain (γ(c)) family in the determination of the effector helper T cell phenotype that naive CD4(+) T cells adopt after being activated and in the function of these helper T cells.The transcription factor c-Maf plays a critical and selective role in IL-4 gene transcription. Little is known about the mechanism that guides c-Maf regulation during early T cell activation. We report that IL-6 but not IL-4 or other cytokines, rapidly up-regulates c-Maf transcription, as early as 3 h after TCR activation in naive CD4(+) T cells. c-Maf induction requires both IL-6- and TCR-initiated signals, and is independent of IL-4/Stat6 signals. Cyclosporin A and FK506, which target calcineurin and thereby inhibit TCR-mediated Ca(2+) signal pathways, block IL-6-mediated c-Maf expression. We show that Stat3 binds the c-maf promoter in CD4 T cells after IL-6 stimulation, and also transactivates the c-maf promoter in reporter gene assays. IL-6 induces similar c-Maf expression in protein kinase Ctheta-deficient CD4(+) T cells. Furthermore, IL-6 enhances IL-4 gene expression very early after TCR activation in both wild-type and Stat6-deficient CD4(+) T cells. Our findings suggest that IL-6 plays a unique role in initiating c-Maf expression after TCR engagement, and may subsequently regulate early IL-4 production and Th2 commitment.A proper balance between Th17 and T regulatory cells (Treg cells) is critical for generating protective immune responses while minimizing autoimmunity. We show that the Tec family kinase Itk (IL2-inducible T cell kinase), a component of T cell receptor (TCR) signaling pathways, influences this balance by regulating cross talk between TCR and cytokine signaling. Under both Th17 and Treg cell differentiation conditions, Itk(-/-) CD4(+) T cells develop higher percentages of functional FoxP3(+) cells, associated with increased sensitivity to IL-2. Itk(-/-) CD4(+) T cells also preferentially develop into Treg cells in vivo. We find that Itk-deficient T cells exhibit reduced TCR-induced phosphorylation of mammalian target of rapamycin (mTOR) targets, accompanied by downstream metabolic alterations. Surprisingly, Itk(-/-) cells also exhibit reduced IL-2-induced mTOR activation, despite increased STAT5 phosphorylation. We demonstrate that in wild-type CD4(+) T cells, TCR stimulation leads to a dose-dependent repression of Pten. However, at low TCR stimulation or in the absence of Itk, Pten is not effectively repressed, thereby uncoupling STAT5 phosphorylation and phosphoinositide-3-kinase (PI3K) pathways. Moreover, Itk-deficient CD4(+) T cells show impaired TCR-mediated induction of Myc and miR-19b, known repressors of Pten. Our results demonstrate that Itk helps orchestrate positive feedback loops integrating multiple T cell signaling pathways, suggesting Itk as a potential target for altering the balance between Th17 and Treg cells.The process of Th cell differentiation toward polarized effector T cells tailors specific immunity against invading pathogens while allowing tolerance against commensal microorganisms, harmless allergens, or autologous Ags. Identification of the mechanisms underlying this polarization process is therefore central to understand how the immune system confers immunity and tolerance. The present study demonstrates that retinoic acid receptor-related orphan receptor C2 (RORC2), a key transcription factor in Th17 cell development, inhibits FOXP3 expression in human T cells. Although overexpression of RORC2 in naive T cells reduces levels of FOXP3, small interfering RNA-mediated knockdown of RORC2 enhances its expression. RORC2 mediates this inhibition at least partially by binding to two out of four ROR-responsive elements on the FOXP3 promoter. Knockdown of RORC2 promotes high FOXP3 levels and decreased expression of proinflammatory cytokines beta form of pro-IL-1, IL-6, IL-17A, IFN-gamma, and TNF-alpha in differentiating naive T cells, suggesting that the role of RORC2 in Th17 cell development involves not only induction of Th17-characteristic genes, but also suppression of regulatory T cell-specific programs. Together, this study identifies RORC2 as a polarizing factor in transcriptional cross-regulation and provides novel viewpoints on the control of immune tolerance versus effector immune responses.Cell differentiation involves activation and silencing of lineage-specific genes. Here we show that the transcription factor Runx3 is induced in T helper type 1 (T(H)1) cells in a T-bet-dependent manner, and that both transcription factors T-bet and Runx3 are required for maximal production of interferon-gamma (IFN-gamma) and silencing of the gene encoding interleukin 4 (Il4) in T(H)1 cells. T-bet does not repress Il4 in Runx3-deficient T(H)2 cells, but coexpression of Runx3 and T-bet induces potent repression in those cells. Both T-bet and Runx3 bind to the Ifng promoter and the Il4 silencer, and deletion of the silencer decreases the sensitivity of Il4 to repression by either factor. Our data indicate that cytokine gene expression in T(H)1 cells may be controlled by a feed-forward regulatory circuit in which T-bet induces Runx3 and then 'partners' with Runx3 to direct lineage-specific gene activation and silencing.The interleukin-2 receptor alpha (IL-2R alpha) chain gene contains a sequence similar to the immunoglobulin (Ig) kappa (kappa) enhancer NF-kappa B binding site. This site, which is bound by the nuclear protein, NF-kappa B, is critical for Ig kappa gene expression. The major T cell nuclear factor that binds to the IL-2R alpha site in vitro appears indistinguishable from NF-kappa B. NF-kappa B binds to IL-2R alpha and kappa sequences with similar affinities; however, only the kappa site potently activates transcription from heterologous promoters. Thus, high-affinity NF-kappa B binding in vitro cannot be equated with transcriptional activation in vivo. Mutation of the NF-kappa B binding site in the context of an IL-2 R alpha promoter construct markedly diminished promoter activity in human T cell lymphotropic virus type I (HTLV-I)-transformed MT-2 cells but not in phorbol myristate acetate-stimulated Jurkat T cells.T helper cells that produce interleukin 17 (IL-17; 'T(H)-17 cells') are a distinct subset of proinflammatory cells whose in vivo function requires IL-23 but whose in vitro differentiation requires only IL-6 and transforming growth factor-beta (TGF-beta). We demonstrate here that IL-6 induced expression of IL-21 that amplified an autocrine loop to induce more IL-21 and IL-23 receptor in naive CD4(+) T cells. Both IL-21 and IL-23, along with TGF-beta, induced IL-17 expression independently of IL-6. The effects of IL-6 and IL-21 depended on STAT3, a transcription factor required for the differentiation of T(H)-17 cells in vivo. IL-21 and IL-23 induced the orphan nuclear receptor RORgammat, which in synergy with STAT3 promoted IL-17 expression. IL-6 therefore orchestrates a series of 'downstream' cytokine-dependent signaling pathways that, in concert with TGF-beta, amplify RORgammat-dependent differentiation of T(H)-17 cells.The role of PI3K in immune cells.Activated STAT4 has an essential role in Th1 differentiation and proliferation that is independent of its role in the maintenance of IL-12R beta 2 chain expression and signaling.The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4.STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function.Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate.Protein kinase C theta (PKCtheta): a key player in T cell life and death.The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes.c-Jun N-Terminal Kinase in Inflammation and Rheumatic Diseases.Displacement of SATB1-bound histone deacetylase 1 corepressor by the human immunodeficiency virus type 1 transactivator induces expression of interleukin-2 and its receptor in T cells.Regulation of the Ifng locus in the context of T-lineage specification and plasticity.TAK1, more than just innate immunity.Differential expression of interleukin-17A and -17F is coupled to T cell receptor signaling via inducible T cell kinase.RORC2 is involved in T cell polarization through interaction with the FOXP3 promoter.The interleukin 2 receptor alpha chain/CD25 promoter is a target for nuclear factor of activated T cells.IL-1β promotes Th17 differentiation by inducing alternative splicing of FOXP3.MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling.A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.Disrupting the intermolecular self-association of Itk enhances T cell signaling.T-bet and eomesodermin play critical roles in directing T cell differentiation to Th1 versus Th17.Smad-dependent cooperative regulation of interleukin 2 receptor alpha chain gene expression by T cell receptor and transforming growth factor-beta.Lck is a relevant target in chronic lymphocytic leukaemia cells whose expression variance is unrelated to disease outcome.T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.Functionally distinct NF-kappa B binding sites in the immunoglobulin kappa and IL-2 receptor alpha chain genes.Both integrated and differential regulation of components of the IL-2/IL-2 receptor system.Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells.NFAT proteins: key regulators of T-cell development and function.MyD88: an adapter that recruits IRAK to the IL-1 receptor complex.Direct interaction between Ras and the kinase domain of mitogen-activated protein kinase kinase kinase (MEKK1).Cutting Edge: Differential Regulation of PTEN by TCR, Akt, and FoxO1 Controls CD4+ T Cell Fate Decisions.Role of Blimp-1 in programing Th effector cells into IL-10 producers.Differential regulation of Foxp3 and IL-17 expression in CD4 T helper cells by IRAK-1.Synergy of IL-12 and IL-18 for IFN-gamma gene expression: IL-12-induced STAT4 contributes to IFN-gamma promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1.NFAT pulls the strings during CD4+ T helper cell effector functions.Cytokines of the γ(c) family control CD4+ T cell differentiation and function.Interleukin (IL) 1beta induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IkappaB kinase alpha pathway targeting activator protein-1.IRAK1 serves as a novel regulator essential for lipopolysaccharide-induced interleukin-10 gene expression.Epigenetic control of the foxp3 locus in regulatory T cells.IL-6, but not IFN-gamma, triggers apoptosis and inhibits in vivo growth of human malignant T cells on STAT3 silencing.Dynamic regulatory network controlling TH17 cell differentiation.Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5.Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation.Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells.Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation.Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells.Regulation of interferon-gamma gene expression by nuclear factor of activated T cells.Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation.T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements.NFATc1 and NFATc2 together control both T and B cell activation and differentiation.IRF4 at the crossroads of effector T-cell fate decision.TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop.Regulation and functions of Blimp-1 in T and B lymphocytes.STAT3 regulates cytokine-mediated generation of inflammatory helper T cells.TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaB.Altered interleukin-12 responsiveness in Th1 and Th2 cells is associated with the differential activation of STAT5 and STAT1.The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-gamma.Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer.Blimp-1 attenuates Th1 differentiation by repression of ifng, tbx21, and bcl6 gene expression.PKC-Theta in Regulatory and Effector T-cell Functions.Smad3 differentially regulates the induction of regulatory and inflammatory T cell differentiation.FOXP3 inhibits activation-induced NFAT2 expression in T cells thereby limiting effector cytokine expression.Th17 differentiation and their pro-inflammation function.The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells.Translocation of PKC[theta] in T cells is mediated by a nonconventional, PI3-K- and Vav-dependent pathway, but does not absolutely require phospholipase C.Lck and the nature of the T cell receptor trigger.SMAD2 is essential for TGF beta-mediated Th17 cell generation.CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer.IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508.Strength of TCR-peptide/MHC interactions and in vivo T cell responses.Interleukin-23-Induced Transcription Factor Blimp-1 Promotes Pathogenicity of T Helper 17 Cells.Protein kinase C-θ promotes Th17 differentiation via upregulation of Stat3.Vav and SLP-76 interact and functionally cooperate in IL-2 gene activation.T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells.Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells.Imaging metabolism of phosphatidylinositol 4,5-bisphosphate in T-cell GM1-enriched domains containing Ras proteins.T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt.The T-cell-receptor signaling network.T cell antigen CD28 binds to the GRB-2/SOS complex, regulators of p21ras.IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state.CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation.The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma.IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation.The Role of the PI3K Signaling Pathway in CD4(+) T Cell Differentiation and Function.Stat3 and Stat4 direct development of IL-17-secreting Th cells.STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+ regulatory T cells and CD4+CD25- effector T cells.IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.Interleukin 2 activates STAT5 transcription factor (mammary gland factor) and specific gene expression in T lymphocytes.Yang Yu Y, Xu Jiangnan J, Niu Yanyan Y, Bromberg Jonathan S JS, Ding Yaozhong YHwang Eun Sook ES, Hong Jeong-Ho JH, Glimcher Laurie H LHMin Lie L, Wu Wenfang W, Joseph Raji E RE, Fulton D Bruce DB, Berg Leslie L, Andreotti Amy H AHYamane Hidehiro H, Paul William E WEMartinez Gustavo J GJ, Zhang Zhengmao Z, Chung Yeonseok Y, Reynolds Joseph M JM, Lin Xia X, Jetten Anton M AM, Feng Xin-Hua XH, Dong Chen CYang Yu Y, Ochando Jordi J, Yopp Adam A, Bromberg Jonathan S JS, Ding Yaozhong YHermann-Kleiter Natascha N, Baier Gottfried GBurgler Simone S, Mantel Pierre-Yves PY, Bassin Claudio C, Ouaked Nadia N, Akdis Cezmi A CA, Schmidt-Weber Carsten B CBYang Xiang-Ping XP, Ghoreschi Kamran K, Steward-Tharp Scott M SM, Rodriguez-Canales Jaime J, Zhu Jinfang J, Grainger John R JR, Hirahara Kiyoshi K, Sun Hong-Wei HW, Wei Lai L, Vahedi Golnaz G, Kanno Yuka Y, O'Shea John J JJ, Laurence Arian ALazarevic Vanja V, Chen Xi X, Shim Jae-Hyuck JH, Hwang Eun-Sook ES, Jang Eunjung E, Bolm Alexandra N AN, Oukka Mohamed M, Kuchroo Vijay K VK, Glimcher Laurie H LHNishihara Mika M, Ogura Hideki H, Ueda Naoko N, Tsuruoka Mineko M, Kitabayashi Chika C, Tsuji Fumio F, Aono Hiroyuki H, Ishihara Katsuhiko K, Huseby Eric E, Betz Ulrich A K UA, Murakami Masaaki M, Hirano Toshio TParmryd Ingela I, Adler Jeremy J, Patel Roopal R, Magee Anthony I AIKwon Myung-Ja MJ, Ma Jian J, Ding Yan Y, Wang Ruiqing R, Sun Zuoming ZKumar P Pavan PP, Purbey Prabhat Kumar PK, Ravi Dyavar S DS, Mitra Debashis D, Galande Sanjeev SParham Christi C, Chirica Madaline M, Timans Jacqueline J, Vaisberg Elena E, Travis Marilyn M, Cheung Jeanne J, Pflanz Stefan S, Zhang Rebecca R, Singh Komal P KP, Vega Felix F, To Wayne W, Wagner Janet J, O'Farrell Anne-Marie AM, McClanahan Terrill T, Zurawski Sandra S, Hannum Charles C, Gorman Daniel D, Rennick Donna M DM, Kastelein Robert A RA, de Waal Malefyt Rene R, Moore Kevin W KWNurieva Roza I RI, Podd Andrew A, Chen Yuhong Y, Alekseev Andrei M AM, Yu Mei M, Qi Xiaopeng X, Huang Hua H, Wen Renren R, Wang Junmei J, Li Haiyan S HS, Watowich Stephanie S SS, Qi Hai H, Dong Chen C, Wang Demin DSong Xinyang X, Gao Hanchao H, Qian Youcun YGarçon Fabien F, Patton Daniel T DT, Emery Juliet L JL, Hirsch Emilio E, Rottapel Robert R, Sasaki Takehiko T, Okkenhaug Klaus KFloess Stefan S, Freyer Jennifer J, Siewert Christiane C, Baron Udo U, Olek Sven S, Polansky Julia J, Schlawe Kerstin K, Chang Hyun-Dong HD, Bopp Tobias T, Schmitt Edgar E, Klein-Hessling Stefan S, Serfling Edgar E, Hamann Alf A, Huehn Jochen JKim Hyoung Pyo HP, Imbert Jean J, Leonard Warren J WJMartins Gislâine G, Calame Kathryn KHawse William F WF, Sheehan Robert P RP, Miskov-Zivanov Natasa N, Menk Ashley V AV, Kane Lawrence P LP, Faeder James R JR, Morel Penelope A PADavis Simon J SJ, van der Merwe P Anton PAPasserini Laura L, Allan Sarah E SE, Battaglia Manuela M, Di Nunzio Sara S, Alstad Alicia N AN, Levings Megan K MK, Roncarolo Maria G MG, Bacchetta Rosa RRaab M M, Pfister S S, Rudd C E CESchuh K K, Twardzik T T, Kneitz B B, Heyer J J, Schimpl A A, Serfling E ETone Yukiko Y, Furuuchi Keiji K, Kojima Yoshitsugu Y, Tykocinski Mark L ML, Greene Mark I MI, Tone Masahide MKim Hyoung-Pyo HP, Kim Byung-Gyu BG, Letterio John J, Leonard Warren J WJSchneider H H, Cai Y C YC, Prasad K V KV, Shoelson S E SE, Rudd C E CEVillalba Martin M, Bi Kun K, Hu Junru J, Altman Yoav Y, Bushway Paul P, Reits Eric E, Neefjes Jacques J, Baier Gottfried G, Abraham Robert T RT, Altman Amnon AGollob J A JA, Murphy E A EA, Mahajan S S, Schnipper C P CP, Ritz J J, Frank D A DAGomez-Rodriguez Julio J, Wohlfert Elizabeth A EA, Handon Robin R, Meylan Françoise F, Wu Julie Z JZ, Anderson Stacie M SM, Kirby Martha R MR, Belkaid Yasmine Y, Schwartzberg Pamela L PLAfkarian Maryam M, Sedy John R JR, Yang Jianfei J, Jacobson Nils G NG, Cereb Nezih N, Yang Soo Y SY, Murphy Theresa L TL, Murphy Kenneth M KMKimura Akihiro A, Naka Tetsuji T, Nohara Keiko K, Fujii-Kuriyama Yoshiaki Y, Kishimoto Tadamitsu TYagi Ryoji R, Junttila Ilkka S IS, Wei Gang G, Urban Joseph F JF, Zhao Keji K, Paul William E WE, Zhu Jinfang JDjuretic Ivana M IM, Levanon Ditsa D, Negreanu Varda V, Groner Yoram Y, Rao Anjana A, Ansel K Mark KMStobbe-Maicherski Natalie N, Wolff Sandra S, Wolff Christian C, Abel Josef J, Sydlik Ulrich U, Frauenstein Katrin K, Haarmann-Stemmann Thomas TRussell M M, Lange-Carter C A CA, Johnson G L GLKoyasu Shigeo SYosef Nir N, Shalek Alex K AK, Gaublomme Jellert T JT, Jin Hulin H, Lee Youjin Y, Awasthi Amit A, Wu Chuan C, Karwacz Katarzyna K, Xiao Sheng S, Jorgolli Marsela M, Gennert David D, Satija Rahul R, Shakya Arvind A, Lu Diana Y DY, Trombetta John J JJ, Pillai Meenu R MR, Ratcliffe Peter J PJ, Coleman Mathew L ML, Bix Mark M, Tantin Dean D, Park Hongkun H, Kuchroo Vijay K VK, Regev Aviv AMathur Anubhav N AN, Chang Hua-Chen HC, Zisoulis Dimitrios G DG, Stritesky Gretta L GL, Yu Qing Q, O'Malley John T JT, Kapur Reuben R, Levy David E DE, Kansas Geoffrey S GS, Kaplan Mark H MHSun Lijun L, Deng Li L, Ea Chee-Kwee CK, Xia Zong-Ping ZP, Chen Zhijian J ZJBeyer Marc M, Thabet Yasser Y, Müller Roman-Ulrich RU, Sadlon Timothy T, Classen Sabine S, Lahl Katharina K, Basu Samik S, Zhou Xuyu X, Bailey-Bucktrout Samantha L SL, Krebs Wolfgang W, Schönfeld Eva A EA, Böttcher Jan J, Golovina Tatiana T, Mayer Christian T CT, Hofmann Andrea A, Sommer Daniel D, Debey-Pascher Svenja S, Endl Elmar E, Limmer Andreas A, Hippen Keli L KL, Blazar Bruce R BR, Balderas Robert R, Quast Thomas T, Waha Andreas A, Mayer Günter G, Famulok Michael M, Knolle Percy A PA, Wickenhauser Claudia C, Kolanus Waldemar W, Schermer Bernhard B, Bluestone Jeffrey A JA, Barry Simon C SC, Sparwasser Tim T, Riley James L JL, Schultze Joachim L JLLozano Teresa T, Villanueva Lorea L, Durántez Maika M, Gorraiz Marta M, Ruiz Marta M, Belsúe Virginia V, Riezu-Boj José I JI, Hervás-Stubbs Sandra S, Oyarzábal Julen J, Bandukwala Hozefa H, Lourenço Ana R AR, Coffer Paul J PJ, Sarobe Pablo P, Prieto Jesús J, Casares Noelia N, Lasarte Juan J JJWu J J, Motto D G DG, Koretzky G A GA, Weiss A ATorgerson Troy R TR, Genin Anna A, Chen Chunxia C, Zhang Mingce M, Zhou Bin B, Añover-Sombke Stephanie S, Frank M Barton MB, Dozmorov Igor I, Ocheltree Elizabeth E, Kulmala Petri P, Centola Michael M, Ochs Hans D HD, Wells Andrew D AD, Cron Randy Q RQGuma Monica M, Firestein Gary S GSYang Xuexian O XO, Panopoulos Athanasia D AD, Nurieva Roza R, Chang Seon Hee SH, Wang Demin D, Watowich Stephanie S SS, Dong Chen CNeumann Christian C, Heinrich Frederik F, Neumann Katrin K, Junghans Victoria V, Mashreghi Mir-Farzin MF, Ahlers Jonas J, Janke Marko M, Rudolph Christine C, Mockel-Tenbrinck Nadine N, Kühl Anja A AA, Heimesaat Markus M MM, Esser Charlotte C, Im Sin-Hyeog SH, Radbruch Andreas A, Rutz Sascha S, Scheffold Alexander AMailer Reiner K W RK, Joly Anne-Laure AL, Liu Sang S, Elias Szabolcs S, Tegner Jesper J, Andersson John JMaitra Urmila U, Davis Sarah S, Reilly Christopher M CM, Li Liwu LKanhere Aditi A, Hertweck Arnulf A, Bhatia Urvashi U, Gökmen M Refik MR, Perucha Esperanza E, Jackson Ian I, Lord Graham M GM, Jenner Richard G RGBrezar Vedran V, Tu Wen Juan WJ, Seddiki Nabila NDai Liang L, Aye Thu Chan C, Liu Xin-Yu XY, Xi Jiajia J, Cheung Peter C F PCHan Jonathan M JM, Patterson Scott J SJ, Levings Megan K MKYang Xuexian O XO, Pappu Bhanu P BP, Nurieva Roza R, Akimzhanov Askar A, Kang Hong Soon HS, Chung Yeonseok Y, Ma Li L, Shah Bhavin B, Panopoulos Athanasia D AD, Schluns Kimberly S KS, Watowich Stephanie S SS, Tian Qiang Q, Jetten Anton M AM, Dong Chen CRegis G G, Icardi L L, Conti L L, Chiarle R R, Piva R R, Giovarelli M M, Poli V V, Novelli F FCross S L SL, Halden N F NF, Lenardo M J MJ, Leonard W J WJNakahira Masakiyo M, Ahn Hyun-Jong HJ, Park Woong-Ryeon WR, Gao Ping P, Tomura Michio M, Park Cheung-Seog CS, Hamaoka Toshiyuki T, Ohta Tsunetaka T, Kurimoto Masashi M, Fujiwara Hiromi HCahill Catherine M CM, Rogers Jack T JTHuang Yingsu Y, Li Tao T, Sane David C DC, Li Liwu LPeng S L SL, Gerth A J AJ, Ranger A M AM, Glimcher L H LHLaurence Arian A, Tato Cristina M CM, Davidson Todd S TS, Kanno Yuka Y, Chen Zhi Z, Yao Zhengju Z, Blank Rebecca B RB, Meylan Françoise F, Siegel Richard R, Hennighausen Lothar L, Shevach Ethan M EM, O'shea John J JJZhou Liang L, Ivanov Ivaylo I II, Spolski Rosanne R, Min Roy R, Shenderov Kevin K, Egawa Takeshi T, Levy David E DE, Leonard Warren J WJ, Littman Dan R DRHuber Magdalena M, Lohoff Michael MTill Kathleen J KJ, Allen John C JC, Talab Fatima F, Lin Ke K, Allsup David D, Cawkwell Lynn L, Bentley Alison A, Ringshausen Ingo I, Duckworth Andrew D AD, Pettitt Andrew R AR, Kalakonda Nagesh N, Slupsky Joseph R JRCorse Emily E, Gottschalk Rachel A RA, Allison James P JPGomez-Rodriguez Julio J, Sahu Nisebita N, Handon Robin R, Davidson Todd S TS, Anderson Stacie M SM, Kirby Martha R MR, August Avery A, Schwartzberg Pamela L PLGilmour K C KC, Pine R R, Reich N C NCWesche H H, Henzel W J WJ, Shillinglaw W W, Li S S, Cao Z ZCimmino Luisa L, Martins Gislaine A GA, Liao Jerry J, Magnusdottir Erna E, Grunig Gabriele G, Perez Rocio K RK, Calame Kathryn L KLMuroi Masashi M, Tanamoto Ken-ichi KNishikomori Ryuta R, Usui Takashi T, Wu Chang-Yu CY, Morinobu Akio A, O'Shea John J JJ, Strober Warren WBettelli Estelle E, Dastrange Maryam M, Oukka Mohamed MHuse Morgan MKishimoto K K, Matsumoto K K, Ninomiya-Tsuji J JZheng Ye Y, Josefowicz Steven S, Chaudhry Ashutosh A, Peng Xiao P XP, Forbush Katherine K, Rudensky Alexander Y AYJain Renu R, Chen Yi Y, Kanno Yuka Y, Joyce-Shaikh Barbara B, Vahedi Golnaz G, Hirahara Kiyoshi K, Blumenschein Wendy M WM, Sukumar Selvakumar S, Haines Christopher J CJ, Sadekova Svetlana S, McClanahan Terrill K TK, McGeachy Mandy J MJ, O'Shea John J JJ, Cua Daniel J DJKiani A A, García-Cózar F J FJ, Habermann I I, Laforsch S S, Aebischer T T, Ehninger G G, Rao A AChang Jihoon J, Burkett Patrick R PR, Borges Christopher M CM, Kuchroo Vijay K VK, Turka Laurence A LA, Chang Cheong-Hee CHHayashi Keitaro K, Altman Amnon ABalasubramani Anand A, Mukasa Ryuta R, Hatton Robin D RD, Weaver Casey T CTMacian Fernando FBrüstle Anne A, Heink Sylvia S, Huber Magdalena M, Rosenplänter Christine C, Stadelmann Christine C, Yu Philipp P, Arpaia Enrico E, Mak Tak W TW, Kamradt Thomas T, Lohoff Michael MBoddicker Rebecca L RL, Kip N Sertac NS, Xing Xiaoming X, Zeng Yu Y, Yang Zhi-Zhang ZZ, Lee Jeong-Heon JH, Almada Luciana L LL, Elsawa Sherine F SF, Knudson Ryan A RA, Law Mark E ME, Ketterling Rhett P RP, Cunningham Julie M JM, Wu Yanhong Y, Maurer Matthew J MJ, O'Byrne Megan M MM, Cerhan James R JR, Slager Susan L SL, Link Brian K BK, Porcher Julie C JC, Grote Deanna M DM, Jelinek Diane F DF, Dogan Ahmet A, Ansell Stephen M SM, Fernandez-Zapico Martin E ME, Feldman Andrew L ALMalhotra Nidhi N, Robertson Elizabeth E, Kang Joonsoo JSMAD family member 2, T-cell surface antigen T4/Leu-3, smad-2, MADR2, Addresses, ted, tmp, Ctla-8, Transcription Factor, Fluorescence-Activated, L3T4, Fluorescence-Activated Cell Sortings, Microfluorometry, Ly-4, SMAD 2, CG2262, Flow Microfluorimetry, IL-17, Cell Sortings, Cytofluorometry, DSmad2, hSMAD2, MADH2, Immune Processes, Transcription, Immune Responses, CANDF6, reference sample, Fluorescence Activated Cell Sorting, Flow Cytofluorometries, Smad-2, Microfluorometries, JV18-1, JV18, smad2, Madr2, SMAD2, Cytokine ML-1, MAD homolog 2, Immune Response, Immune, Pathologies, Mothers against DPP homolog 2, Flow, C87042, Flow Microfluorometries, Cytometry, Smad2, ML1, Immune Process, Flow Cytofluorometry, Cytometries, Sortings, Controlled, 7120426M23Rik, DmelCG2262, Cell Sorting, Cytotoxic T-lymphocyte-associated antigen 8, data, Controlling, CTLA8, Fluorescence-Activated Cell Sorting, Stat5, Process, T-cell surface antigen T4|Leu-3, Il17, Madh2, Flow Cytometries, Factor, Cell, Microfluorimetry, Cytokine, ML-1, T-cell differentiation antigen L3T4, IL17, dSMAD2, l(1)G0348, DSMAD2, XSmad2, Sad, Flow Microfluorometry, dSmad2, hMAD-2, Cytofluorometries, CTLA-8, Factors, mMad2, Mad-related protein 2, T-cell surface glycoprotein CD4, Ctla8, CD4mut, sad, STAT5, Fluorescence-Activated Cell, dsmad2, IL17., IL-17F, IL-17A, SMOX, MGF, Sorting, Response, CD4, AA959963, smoxUVO Gene Mutation, DmelCG4088, DmErk, pp44mapk, H. pylori Positive, Kinship, A4, ERBB2 Amplification, phosphorylation, p38a, Dm SRC41, Positive Charge, RET/PTC Rearrangement, Hepatitis C Virus RNA Positive, p53 Mutation, SRC 29A, Associations, PGR Positive, Life Cycle, Kinase, phosphokinase activity, SEM, p38A, Methylated MGMT Promoter, calcio, Dsrc28C, ERA Positive, perturbation, Kinship Network, G Protein Subunit Alpha q Gene Mutation, IDH Gene Mutation, CD324 Gene Mutation, Hepatitis B Virus Core Antibody Positive, c-KIT Positive, Flavoprotein Subunit of Complex II Positive, Dsor2, B7H1 Positive, BEK Gene Mutation, Biochemical Diagnosis, node-positive, Cadherin 1 Gene Mutation, ESTRB Positive, XH2 Gene Mutation, LYK, Dsrc29A, NOR-1, decreased, Catenin Beta 1 Gene Mutation, ER Beta Positive, Hck-3, Telomerase Reverse Transcriptase Gene Promoter Mutation, LATHEO, Methylated MGMT Gene Promoter, DmMPK2, Ca, Tk5, ERK-A, Ligand, Adapter Device, dpERK, Human Immunodeficiency Virus Positive, KGFR Gene Rearrangement, c-erbB2 Gene Amplification, pp58lck, transcription-coupled repair, ERK-1, ERK-2, B-RAF Gene Rearrangement, Anti-HBc Positive, DmMAPK, Normalcy, dp-ERK, Hepatitis B Virus Surface Antibody Positive, Estrogen Receptor Alpha Positive, DmIKKgamma, SDHIP Positive, dIKK, Emt, HD-29, ET, pMAPK, FGFR-2 Gene Rearrangement, FLT2 Gene Mutation, FGFR-1 Gene Rearrangement, External, RET Gene Rearrangement, Disruption, Tec29A, activation, NRAS Gene Mutation, ECAD Gene Mutation, Clustering Analysis, IKK-gamma, c-SRC, l(2)41Ac, T-cell receptor signalling pathway, EST2 Promoter Mutation, Mtap2k, Present, Component, ESR Positive, PDCD1L1 Positive, SmokTcr, C78273, DmelCG7524, CT34260, Positive EBV Serum Test, MOUSE, dpERk, src28C, IDH Gene Family Mutation, Info, SAPK, N-RAS Gene Mutation, HER2/Neu Amplification, Dominant negative form of Smok, Mouse, T Cell, KRAS Gene Mutation, Expression of PD-L1, vr6, Thymus Derived Lymphocyte, 9030612K14Rik, Induced, Tcsk, D-p38 MAPK, SDHF Positive, Nuclear Receptor Subfamily 3 Group A Member 2 Positive, BRCA1-Associated Protein 1 Gene Mutation, CDHE Gene Mutation, Dm SRC2, Su(Raf)1, Dm SRC1, Succinate Dehydrogenase [Ubiquinone] Iron-Sulfur Subunit, Tec kinase, Hepatitis B Virus Surface Antigen Positive, TCR signaling pathway, Rlk protein, dMPK2, Factor IV, Mus musculus domesticus, MAM, G Protein Subunit Alpha 11 Gene Mutation, Erk, Cluster Analysis, B7-H Positive, Cadherin-Associated Protein, Src42a, MGMT Gene Methylation, Hepatitis B Core Antibody Positive, PCBC, Orc3, erk, BEK Gene Rearrangement, RET Rearrangement, RAD54 Homolog Gene Mutation, itk protein, rll, Lskt, pp60c-src, HER-2 Gene Amplification, STK26, p38-2, myelin basic protein kinase activity, DSRC64, Positive EBV Test, DRT, Esrk1, Family Research, CG44128, PR Positive, Hepatitis B Surface Protein Antigen Positive, stress-activated kinase activity, MAP-2 kinase activity, Estrogen Receptor Positive, lat, B-RAF1 Gene Rearrangement, ATRX, BRAF Gene Rearrangement, Tsk, Adapter (Adaptor), stress-activated protein kinase activity, Expression Positive, FLG Gene Mutation, PAX8 Rearrangement, CG7873, Androgen Receptor Positive, HGFR Gene Amplification, ESR1 Positive, tec protein, Dsrc42A, MET Gene Amplification, c-MET Gene Amplification, ER-Alpha Positive, l(2)k10108, Calcium, Methylated MGMT, CG12559, Dmikkgamma, P42MAPK, ERG Rearrangement, dpERK1, HBsAg Positive, House Mice, CG16910, BB161688, TERT Gene Promoter Mutation, Enzymatic Activity, High, Ret Proto-Oncogene Rearrangement, AU018647, Primary Cause of Death, IDH Mutation, 1p/19q Co-deletion, SDHA Positive, Drug Product Component, Q Polypeptide Gene Mutation, Succinate Dehydrogenase [Ubiquinone] Flavoprotein Subunit, Relatives, Dtk5, p44mapk, SAP kinase activity, Dsrc64B, Estrogen Receptor 2 Positive, Networks, mRNA Expression, XNP Gene Mutation, O-6-Methylguanine-DNA Methyltransferase Gene Promoter Methylation, Protein-Tyrosine Kinase, ER Positive, v-Ets Erythroblastosis Virus E26 Oncogene Like Gene Rearrangement, Mpk2, Calcium 40, Mus domesticus, Expression Detected, Protein Tyrosine Kinase, p42mapk, PP2030, protein expression, p38 alpha, HRAS1 Gene Mutation, G-ALPHA-q Gene Mutation, SR2-1, BAP1 Gene Mutation, Mammals, Tyrosine-Specific Protein Kinase, Dmel_CG7873, v-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 Gene Mutation, IKKg, TP53, Abnormal, KEY, gene expression, increased, Sequencing Adapter, Estrogen Receptor Beta Positive, twm, membrane region, src64B, hypoplasia, DOG1 Positive, DERK-A, CG7524, xsrc, E(sina)7, ETV Family Gene Rearrangement, Ets Variant Family Rearrangement, Rl, c-src/fps, FLT2 Gene Rearrangement, Rearrangement identified, FGFR3 Gene Rearrangement, MP kinase activity, ECT1 Gene Mutation, Estrogen Receptor 1 Positive, Fibroblast Growth Factor Receptor 2 Gene Mutation, Had, IDH Family Mutation, Subsequent, CD333 Gene Rearrangement, ATP - protein phosphotransferase (MAPKK-activated) activity, dERK, Has, ATRX Gene Mutation, Src29A, ERG Gene Rearrangement, SLP76, Mnk1, Primary Tumor, Mapk, mouse, ERK1, ERK2, mapk1a, HER2 Gene Mutation, membranous organ component, results, DmelCG44128, Gene Expression, D-p38a, SLP-76, p41mapk, Hepatitis B Surface Antibody Positive, T-Cell, MapK, mapk1b, Kenny, HIV Positive, LAT1, PRCDTH, P38, CG4088, Filiation, SRC 64B, Su(D-raf)1, erk2, Dscr28C related (Drosophila) protein, HIV positive, 1p/19q Codeletion, Adaptor, ORC, POSITIVE, ERKa, Tyrosine Protein Kinase, Guanine Nucleotide Binding Protein (G Protein), Yes, BcDNA:RE08694, Src2, Src1, l(2R)EMS45-39, dSrc, SDH2 Positive, CAPB, DmelCG12559, ERBB2 Gene Mutation, p38, Tyrosine Kinase, domesticus, DpErk, ERKA, calcium, HUMKER1A, DMDA, DmelCG16910, Expressed, ER-Beta Positive, p41, Clustering, p40, P44MAPK, p44, HRAS Gene Mutation, D-Src64B, Harvey Rat Sarcoma Viral Oncogene Homolog Gene Mutation, Regulation, zebrafish, p56lck, BRAF Rearrangement, CDH1 Gene Mutation, Thymus-Dependent Lymphocytes, D-src, Anti-HBs Positive, c-erbB2 Gene Activation, Network, supernumerary, p56Lck, dp38a, Hek5, HS44KDAP, Fp Positive, House, subnumerary, Fibroblast Growth Factor Receptor 1 Gene Rearrangement, integral component of membrane, DTec29, OGD Gene Mutation, nrs, dsrc, Anti-HBcAb Positive, Hep C RNA Positive, Stimulation., tiny, p42-MAPK, IKK[[gamma]], p60-Src, CD274 Antigen Positive, Epithelial Gene Mutation, primary, MET Proto-Oncogene, study, Calcium-40, AI573420, Research, Self, Swiss, SWS Gene Mutation, TAOS2 Positive, Lecithinases, T-lymphocyte receptor signaling pathway, Transphosphorylase, Methylguanine-DNA Methyltransferase Gene Promoter Methylation, CG18732, Neuroblastoma RAS Viral Oncogene Homolog Gene Mutation, H-ras Gene Mutation, Erk-1, Txk tyrosine kinase, HSpin1, ETV Gene Rearrangement, IKK, CD332 Gene Rearrangement, region of membrane, Ets Variant Gene Family Rearrangement, HER2 Gene Amplification, HD-358, SRC 42A, Family, dsrc29A, DSrc64B, SRC42A, CTNNB Gene Mutation, progesterone receptor positive, RASH1 Gene Mutation, Possess, small, membrane, Nor1, ert1, Regulatory, Anti-Hepatitis B Virus Core Antibody Positive, T-lymphocyte receptor complex, src42a, l(2)vr6, Kalzium, Lsk, 2.7.11.1, Protein Functional Component, NR3A2 Positive, src42A, MGMT Gene Promoter Methylation, whole membrane, MBP kinase I activity, src64b, DmORC3, l(2)49Fd, Insects, TMEM16A Positive, CG8049, Catenin Beta-1 Gene Mutation, MGMT Methylation, AR Positive, DSrc42A, Xp42, TCR, transmembrane, FMS-Like Tyrosine Kinase 2 Gene Mutation, MINOR, HIV Positivity, Normality, Mast/Stem Cell Growth Factor Receptor Kit Positive, Kinases, mitogen activated kinase activity, Su(Raf)2B, FGFR-2 Gene Mutation, Calcium-Dependent Adhesion Protein, PH Domain, Laboratory Mice, present in greater numbers in organism, Coagulation Factor IV, D-ERK, ERT1, ERT2, SCARMD2, p44-ERK1, TEC, HBs Antigen Positive, CD274 Molecule Positive, MAP kinase 1 activity, GTPase Gene Mutation, fic, src-1, src-4, Anti-HBsAb Positive, extracellular signal-regulated kinase activity, Beta Gene Mutation, Laboratory, Tyro5, Progesterone Receptor Positive, FGFBR Gene Rearrangement, House Mouse, Compared, LeMPK3, p56-lt-lck-gt-, p44mpk, btk29A, Dp38, Nuclear Receptor Subfamily 3 Group A Member 1 Positive, SAPK2, Sem, Erg-3 Gene Rearrangement, CD332 Gene Mutation, Ha-ras Gene Mutation, average, MAP-k, EXPRESSED, HRas Proto-Oncogene, pp42, TRT Promoter Mutation, T-Cells, EK5, GAQ Gene Mutation, Met Proto-Oncogene (Hepatocyte Growth Factor Receptor) Gene Amplification, Comparison, pp36, FGFR1 Gene Rearrangement, PD-L1+, sem, T lymphocyte receptor signaling pathway, NEU Gene Mutation, v-raf Murine Sarcoma Viral Oncogene Homolog B1 Gene Rearrangement, FGFR3 Gene Mutation, SDHB Positive, K-RAS Mutation, CD331 Gene Rearrangement, Phospholipase, C-HA-RAS1 Gene Mutation, MET Amplification, ATP Phosphotransferases, ZNF-HX Gene Mutation, ERBB2 Gene Amplification, Blood Coagulation Factor IV, LOINC Axis 1, Beta Catenin Gene Mutation, Pleckstrin-Homology Domain, dpErk, Coagulation, Followed By, CHN, Recruitment, integral to membrane, SPIN1, PMK-2, PMK-1, CG18355, PMK-3, Alpha 11 Gene Mutation, CD331 Gene Mutation, ERB Positive, Cadherin, EMT, JKT4 Gene Rearrangement, pMapK, D-MPK2, SK2-4, Regulated, Pleckstrin Homology Domain, CMC1 Gene Mutation, DmelCG5475, P53 Gene Mutation, DmERKA, PSCTK4, rl/MAPK, Guanine Nucleotide-Binding Protein, PAX8 Gene Rearrangement, PSCTK2, Outside, NR3A1 Positive, MRE5, Swiss Mouse, Keratinocyte Growth Factor Receptor Gene Rearrangement, HER2 Amplification, Lck1, CT2415, human, CD333 Gene Mutation, recruitment (subjects), Positive Epstein-Barr Virus Test, T cell, primary tumor, FGFBR Gene Mutation, TCS1 Promoter Mutation, c-src, SPINL, BFGFR Gene Mutation, p44erk1, HCV RNA Positive, 12559, dIKK-gamma, ER+, EK2-1, Inducible, Receptor Tyrosine Kinase Gene Amplification, T-Lymphocytes, FGFR1 Gene Mutation, AA407128, Functional Component, p55 Gene Rearrangement, FLG Gene Rearrangement, src64, PDCD1LG1 Positive, DmIKK-gamma, Prkm1, Prkm3, Higher, ERK, Normalities, PRKM1, PRKM3, ETV Rearrangement, androgen receptor positive, PRKM2, HBs Positive, ORC3L, p38Ka, Positive Number, ligand, vr-6, Inducing, LPFS1, positive test result, ORC3, v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog Gene Mutation, GNAQ Gene Mutation, PD-L1 Positive, Tec protein, CTNNB1 Gene Mutation, FGFR2 Gene Rearrangement, ANO1 Positive, DSrc64, RAD54 Gene Mutation, dtk-5, Expression, Tec29, LAT, CD117 Positive, FGFR2 Gene Mutation, Dp38a, Helicobacter pylori Positive, Adapter, Application Adapter, ESRB Positive, Phosphorylations, dtk5, DSrc28, Primary, Cell, Family Members, IKKgamma, Positive Finding, TCR complex, Have, GNA11 Gene Mutation, mapk2, mapk1, S13, Induce, Hepatocyte Growth Factor Receptor Gene Amplification, T-lymphocyte receptor signalling pathway, CT41718, T lymphocyte receptor complex, Biochemical Response, Src, IMD22, DMDA1, underdeveloped, Regulator, HBcAb Positive, Information, increased number, Tumor Protein p53 Gene Mutation, AW259666, IP Positive, Hepatitis B Surface Antigen Positive, N-RAS Mutation, FLT-2 Gene Mutation, ETS Transcription Factor ERG Gene Rearrangement, BED-Biochemical Evidence of Disease, src, dpMAPK, Families, src42, Su1, CEK Gene Mutation, Lcktkr, regulation, Alpha-11 Gene Mutation, Chromatin Remodeler Gene Mutation, Murine, TC-NER, Fibroblast Growth Factor Receptor 1 Gene Mutation, Hepatitis C Viral RNA Positive, pp60v-src, Biochemical, FLT-2 Gene Rearrangement, CSMF, JKT4 Gene Mutation, T-Lymphocyte, D-p38, AR+, KRAS Mutation, Highly, ESR-Beta Positive, EC 2.7.10, Fibroblast Growth Factor Receptor 2 Gene Rearrangement, FGFR-3 Gene Rearrangement, P44ERK1, mitogen-activated protein kinase activity, KGFR Gene Mutation, mpk2, present in fewer numbers in organism, mpk1, Family Life Cycle, Key, estrogen receptor positive, Erk/Map kinase, Protein Expression, transcription-coupled NER, Alpha Thalassemia/Mental Retardation Syndrome X-Linked Gene Mutation, Swiss Mice, btk, tec-family kinase, T Cells, Tyrosine-Protein Kinase, ASV, c-Met Gene Amplification, DERK, PR+, FMS-Like Tyrosine Kinase 2 Gene Rearrangement, Dmp38a, Anti-Hepatitis B Core Antibody Positive, B7 Homolog 1 Positive, MBP kinase II activity, Beta 1 (88kD) Gene Mutation, Positive, Family Life Cycles, CG5475, ATP, MNK1, MAP kinase 2 activity, Anti-HBs Antibody Positive, TP53 Gene Mutation, csrc, DmHD-29, Erk1, 1p/19q co-deletion, Erk2, KIT Proto-Oncogene Tyrosine Protein Kinase Positive, v-Ha-ras Harvey Rat Sarcoma Viral Oncogene Homolog Gene Mutation, Positive Estrogen Receptor, D-P38a, HBsAb Positive, Su(phl)1, K-SAM Gene Mutation, IL2-inducible T-cell kinase, Succinate Dehydrogenase Complex Flavoprotein Subunit A Positive, Induction, YT16, Primary Neoplasm, MAPK, tec protein tyrosine kinase, Succinate Dehydrogenase Complex Iron Sulfur Subunit B Positive, KRAS2 Gene Mutation, mapk, Biochemical Markers Diagnosis, Mus musculus, Transphosphorylases, PTK, membrane of organ, Element, Paired Domain Gene 8 Gene Rearrangement, Stimulation, SRC1, Programmed Cell Death 1 Ligand 1 Positive, ESR2 Positive, Hepatitis C RNA Positive, T lymphocyte receptor signalling pathway, AI323664, Type 1, DpERK, Life Cycles, ErkA, Positive Laboratory Test Result, Paired Box 8 Gene Rearrangement, Stimulating, src4, Health, LCAM Gene Mutation, E-Cadherin Gene Mutation, Lecithinase, T-cell receptor complex, src1, Arc-1 Gene Mutation, src2, N-SAM Gene Mutation, N-SAM Gene Rearrangement, pERK, accessory, CD274 Positive, Dsrc, DmelCG8049, Family Member, Enzyme Activity, GroupII, KRAS-2 Gene Mutation, Dsrc41, PDL1 Positive, C-src1, CG14471, KIT Positive, Anti-HBc Antibody Positive, TERT Promoter Mutation, Compare, C-src2, KAL2 Gene Mutation, TYPE, C-src4, ECT1 Gene Rearrangement, DSrc, DAGA4, Responder protein Smok-Tcr, Anoctamin-1 Positive, DmHD-358, reduced, FGFR-3 Gene Mutation, 20Ca, TEC protein, Anti-Hepatitis B Virus Surface Antibody Positive, Stimulated, dmIKKgamma, Next, Externally, CG14225, HIV test positive, SCG3, Mice, Phosphotransferase, Erb-B2 Receptor Tyrosine Kinase Gene Mutation, BFGFR Gene Rearrangement, Src64, tec29, Dsrc64, Fibroblast Growth Factor Receptor 3 Gene Mutation, xp42, T-cell receptor signaling pathway, Cadherin 1, E-Cadherin (Epithelial) Gene Mutation, HER2/neu Gene Mutation, BRCA1 Associated Protein 1 Gene Mutation, decreased number, v-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog Positive, p42 mitogen-activated protein kinase activity, ATP:protein phosphotransferase (MAPKK-activated) activity, p56<lck>, Positive Lymph Node, Following, C-H-RAS Gene Mutation, DmERK-A, OGD Gene Rearrangement, Kinship Networks, KAL2 Gene Rearrangement, SDH1 Positive, ER Alpha Positive, UCHL2 Gene Mutation, RAD54L Gene Mutation, NOR1, Src42, GNA-11 Gene Mutation, Src41, CEK Gene Rearrangement, DMPK2, prkm2, CT39192, prkm1, Loss of Chromosomes 1p/19q, ESTRR Positive, Phosphotransferases, K-SAM Gene Rearrangement, LGMD2C, Exogenous, p38delta, LSK, del(1p/19q), Mus, group 2, Fibroblast Growth Factor Receptor 3 Gene Rearrangement, Extramural, DmOrc3, cytoplasmic tyrosine kinase, ESRA Positive, T lymphocyte, ERBB2 Mutation, Tcr, ETV Family Rearrangement, DmelCG14225, Beta-Catenin Gene Mutation, GA11 Gene Mutation, Paired Box Gene 8 Gene Rearrangement, TP2 Promoter Mutation, btk29a, Protein Component, Tec tyrosine kinase, ORAOV2 Positive, Dmel_CG14471, EY2-2, Biochemical Evidence of Disease, MAPK2, MAPK1, Insect, dp38, BAP1 Mutation, c-K-ras Gene Mutation, Ert2, EPHT3, p44-MAPK, FGFR-1 Gene Mutation, Tec, variable, T-cell-restricted tyrosine kinase Txk, Mitochondrial Positive, Laboratory Mouse7120426M23Rik, DmelCG2262, Cytotoxic T-lymphocyte-associated antigen 8, CTLA8, SMAD family member 2, Stat5, smad-2, MADR2, Il17, Madh2, ted, tmp, Ctla-8, dSMAD2, IL17, l(1)G0348, DSMAD2, SMAD 2, XSmad2, Cell., CG2262, Sad, IL-17, dSmad2, hMAD-2, DSmad2, hSMAD2, MADH2, CTLA-8, mMad2, Mad-related protein 2, Smad-2, JV18-1, JV18, smad2, Ctla8, sad, STAT5, Madr2, dsmad2, SMAD2, IL-17A, MAD homolog 2, SMOX, MGF, Mothers against DPP homolog 2, Smad2, AA959963, smoxdP60, CG5373, ATVPS34, Vps34, PI3K92E, PI3K, Pi3K_59F, Dp110, BcDNA:LD15217, type I phosphatidylinositol kinase activity, VPS34, 11621, phosphatidylinositol 3-kinase, PI-3 kinase, p110-alpha, PIK3, PHOSPHATIDYLINOSITOL 3-KINASE, Pi3Kp60, dVps34/PI3K59F, DmelCG2699, Roles, F8A5.4, p60, PI3K-dp110, Concepts, dPI3K, Cell., PHOSPATIDYLINOSITOL 3-KINASE, anon-92Ed, phosphatidylinositol 3-kinase activity, Dp110/PI3K, PI3K-68D/E, class I, Dp60, Pi3K92D, CG4141, PI3K_59F, catalyst activity, Pi3k, PI3-kinase activity, PI3'K, PI[[3]]K, Pi3Kp110, PI3Kgamma, P110BETA, MCAP, PI3K-68D, p55alpha, Immune, PI3K21B, Role Concepts, PI3K 68D, Pi3K, PI3k, MCM, MCMTC, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, Cpk, dP110, dVps34, PI3K68D, AA414921, P110DELTA, p120, class II, PtdIns-3-kinase activity, rea, type III phosphoinositide 3-kinase activity, p50alpha, p110, Vps34p, CG2699, PI(3)K, vacuolar protein sorting 34, DmelCG5373, cpk, Concept, dPIK, 1-phosphatidylinositol 3-kinase activity, PI3K-92E/Dp110, PIK3C1, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, Role Concept, C530050K14, CWS5, vps34, type-1 PI3K, Role, dp110, PI3CG, PI-3-K, CG11621, PI3K-59F, p85alpha, PI3K-Dp110, class III, DmelCG11621, PI3K 68_D, p110gamma, DmelCG4141, F8A5_4, APDS, p110D, CLOVE, DmVps34, IMD14, PI3K_68D, PI3KBETA, PI3K-92D, Dmp110, p120-PI3K, droPIK57falseCorral2021 - Interplay between SMAD2 and STAT5A regulating IL-17A/F expression in Th cells.IL-17A and F are critical cytokines in anti-microbial immunity but also contribute to auto-immune pathologies. Recent evidence suggests that they may be differentially produced by T-helper (Th) cells but the underlying mechanisms remain unknown. To address this question, a logical model containing 82 components and 136 regulatory links was developed and calibrated with original flow cytometry data using naive CD4+ T cells in conditions inducing either IL-17A or F. Model analyses led to the identification of the transcription factors NFAT2A, STAT5A and Smad2 as key components explaining the differential expression of IL-17A and IL-17F, with STAT5A controlling IL-17F expression, and an interplay of NFAT2A, STAT5A and Smad2 controlling IL-17A expression.2021-04-062021-04-062021-01-15MODEL21011500011691187023467089773727515713622193868931268128425855357185153652290503474798819454765230802041962604711956228232323982652829112006974162757662010378111163226186849232115110415790681202372891719584520969595115207982065668311801649107023081988737477448231905029022941947151258331758153717277312123703722334160526441347230284072184178512023369193808241754429215465816181642222258603215728480174939599430229174042711860700426750311198186501807098221278738245341902507379222318729183709212526120620399120173633002583396317676043247821592412775321505216211908971592867929196709263247681956434218270368867370611754814200721261815713312660731204277701800669817298177249752097636161608767159925970906560091548895886018113671136260101159960015438676837966769113666859597160225972191001136562045995599377761136410471102587562600560191177259816112256117967120366171934616404104733372102606119348165317006524777516787777128581887461066008P01137P14784P51692P42224P31785Q9UL17P60568P28482P01579Q15796P01100P84022Q13233P42229P42701O43318P40189Q99665Q5VWK5Q14765P05412Q9NPH3Q01826P14778Q13469Q01196P40763Q00653P35398O75444Q9HBE4P08887Q99836Q16552P51617P61073Q9Y4K3Q08881O75626Q96PD4Q13761O95936P51449Q15306P35869P10747P33681P06239O95644P01730P43403Q12968Q9BZS1O43561P15498Q07889P0158910.1186/s43556-021-00034-3