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Transcription Factor p73 Regulates Th1 Differentiation

ABSTRACT: Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic, and autoimmune diseases. To identify factors contributing to these response differences, we analyzed the phenotypic profiles of in vitro-differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis indicated that the p53 family protein, p73, affected Th1 differentiation. In cells differentiated under Th1 conditions in vitro, we demonstrated that p73 was a negative regulator of IFNγ production, and this effect required the DNA-binding activity of p73. p73 bound within the gene body or upstream of many genes that affect Th1 differentiation and regulated their expression (e.g., Ifng and Il12rb2). Furthermore, in experimental autoimmune encephalitis, which is a mouse disease model of multiple sclerosis, p73-deficient mice had increased IFNg production and decreased disease severity, whereas in the adoptive transfer model of inflammatory bowel disease, transfer of p73- deficient naïve CD4+ T cells into WT Rag2-/- hosts resulted in increased Th1 responses and enhanced disease severity compared to transfer of WT cells. These studies identify p73 as a regulator of immune responses and indicate that its dysregulation may play a role in susceptibility to autoimmune disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE144496 | GEO | 2020/01/29

REPOSITORIES: GEO

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Transcription Factor p73 Regulates Th1 Differentiation

Project description:T helper (Th) cells play critical functions in response to infectious, allergic, and autoimmune diseases. Upon exposure to a given infectious agent or stimulus, different individuals vary in their Th cell responses, influencing the final disease outcome. To investigate the genetic factors that contribute to such differential immune responses, we performed a haplotype-based computational genetic analysis based on the phenotypic profiles of in vitro differentiated Th1 cells from 16 inbred mouse strains. And we identified genes including that encoding the p53 family protein, p73, with SNP patterns that correlated with the quantitative difference in IFNγ expression. Overexpression of p73 inhibited Th1 differentiation, as evaluated by reduced IFNγ expression, whereas shRNA knockdown or knockout of the p73 gene augmented IFNγ production. An inhibitory effect of p73 on Th1 differentiation was also observed in Stat1-/- cells, indicating that the effect was at least partially independent of STAT1. The DNA-binding activity of p73 is required for its inhibitory effect on IFNγ expression, as deletion of p73 DNA binding domain abolished IFNγ inhibition. A global gene expression analysis showed that 206 genes are differentially expressed more than two-fold in response to p73 overexpression, and 55 of these are direct target genes of p73 in Th1 cells, based on ChIP-seq analysis. p73 binding peaks were identified at a range of genes, including at the Il12rb2, Il24, and Il2ra loci, and p73 was implicated for regulating these genes based on reporter constructs containing WT or mutant p73 binding sites. Furthermore, p73 deficient mice had reduced disease severity in MOG induced EAE, with increased IFNg production from spinal cord infiltrating cells. Thus, p73 is a novel regulator of IFNγ expression, revealing a previously unanticipated role for p73 in Th1 cell differentiation.

2019-12-18 | GSE107368 | GEO

Immune Gene Expression Profile of Tr1 Skewed Tregs

Project description:IL-12 and IL-18 synergize to promote TH1 responses and have been implicated as accelerators of autoimmune pathogenesis in type 1 diabetes (T1D). We therefore investigated the influence of these cytokines on phenotype and function of immune cells that are involved in disease progression. To understand how IL-12 and IL-18 may synergize to impair Treg function and phenotype, we conducted transcriptional profiling of Treg expanded under normal conditions or in the presence of IL-12 and IL-18. This analysis revealed increased expression of IFNG, GZMB, GZMA, and IL18RAP and decreased FOXP3 in Tregs expanded with IL-12 and IL-18.

2020-08-31 | GSE143690 | GEO

Restraint of IFN-γ expression through a distal silencer CNS–28 for tissue homeostasis

Project description:Interferon-gamma (IFN-gamma) is a key cytokine in response to viral or intracellular bacterial infection in mammals. While a number of enhancers are described to promote IFN-gamma responses, no silencers for the Ifng gene have been identified. By examining H3K4me1 histone modification in naïve CD4+ T cells within Ifng locus, we identified an unrecognized silencer (CNS–28) that is responsible for restraining Ifng expression. Mechanistic study further demonstrates that CNS–28 maintains Ifng silence by diminishing enhancer-promoter interactions within Ifng locus in a T-bet independent manner. Functionally, CNS–28 restrains Ifng transcription in Th1, Tc1, and NK cells during both innate and adaptive immune responses. Moreover, CNS–28 deficiency resulted in repressed type 2 responses due to elevated IFN-gamma expression, shifting Th1 and Th2 paradigm. Thus, CNS–28 activity ensures immune cell quiescence by cooperating with other regulatory cis elements within the Ifng gene locus to minimize autoimmunity.

2023-03-01 | GSE204946 | GEO

Foxp3-specific deletion of CREB generates Th2 biased ST-2 positive regulatory T-cells with enhanced IL-10 production and suppressive capacity

Project description:Regulatory T cells (Tregs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains Treg identity. The transcriptional activator CREB critically stabilizes Foxp3 expression in vitro. Here we demonstrate that in mice with a Foxp3-specific knockout of CREB, Tregs show a reduced Foxp3 expression in vivo, but surprisingly enhanced expression of IL-13, IL-10, ST-2 and CREM. This rendered such Tregs highly suppressive in vitro and prevents disease activity in Th1 models like T cell mediated transfer colitis in an IL-10 dependent way. On the other hand, type 2 B cell responses were enhanced resulting in high IgE levels and susceptibility towards experimental asthma. Our data suggest that CREB expression in Tregs is important for the balance between Th1 and Th2 responses by regulating ST-2 and IL-10.

2022-12-01 | GSE157693 | GEO

Transcription Factor p73 Regulates Th1 Differentiation

Project description:Transcription Factor p73 Regulates Th1 Differentiation

| PRJNA419910 | ENA

Transcription Factor p73 Regulates Th1 Differentiation

Project description:Transcription Factor p73 Regulates Th1 Differentiation

| PRJNA603788 | ENA

The X chromosome gene Kdm6a modulates multiple immune response genes in CD4+ T cells and is disease promoting in autoimmune disease

Project description:Multiple sclerosis (MS) is a T-cell mediated autoimmune disease that has a sexually dimorphic pattern in disease susceptibility. Consistent with many autoimmune diseases, females are more susceptible than males to MS. Sexual dimorphisms may be due to differences in sex hormones, sex chromosome genes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape the dosage compensation mechanism of X inactivation and have higher expression in females (XX) compared to males (XY). According to the high throughput analysis, the top sexually dimorphic gene with higher expression in CD4+ T cells from females (vs. males) and from XX mice (vs. XY) was Kdm6a, a histone demethylase and transcription factor on the X chromosome. Deletion of Kdm6a specifically in CD4+ T cells ameliorated clinical disease and reduced neuropathology in the classic CD4+ T cell mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). Global transcriptome analysis in CD4+ T cells from EAE mice with a specific deletion of Kdm6a showed upregulation of Th2 and Th1 activation pathways and downregulation of neuroinflammation signaling pathways. Together, this demonstrates that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.

2019-10-18 | GSE121703 | GEO

The X chromosome gene Kdm6a modulates multiple immune response genes in CD4+ T cells and is disease-promoting in autoimmune disease

2019-10-18 | GSE128615 | GEO

Differential transcription network analysis for Fusarium head blight disease of barley in combination with drought stress

Project description:For improvement of stress and disease resistance of barley, this global transcriptomic study focuses on how drought conditions affect Fusarium head blight (FHB) severity in spring barley. In general, drought-stress prior to Fusarium culmorum infection reduced FHB-susceptibility. This study gives evidence, that FHB-severity and strength of drought responses is variety-dependent under complex stress situations.

2023-09-15 | GSE223521 | GEO

Retinoic acid signaling constrains the plasticity of Th1 cells and prevents development of pathogenic Th17 cells [Affymetrix experiments]

Project description:CD4+ T cells differentiate into phenotypically distinct T-helper cells upon antigenic stimulation. Regulation of plasticity between these CD4+ T-cell lineages is critical for immune homeostasis and prevention of autoimmune diseases. However, the factors that regulate lineage stability are largely unknown. Here we investigate a role for retinoic acid (RA) in the regulation of lineage stability using T helper 1 (Th1) cells, traditionally considered the most phenotypically stable Th subset. We found that RA, through its receptor RARa, sustains stable expression of Th1 lineage specifying genes as well as repressing genes that instruct Th17 cell fate. RA signaling is essential for limiting Th1 cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. Our studies identify RA-RARa as a key component of the regulatory network governing Th1 cell fate and define a new paradigm for the development of pathogenic Th17 cells. These findings have important implications for autoimmune diseases in which dysregulated Th1-Th17 responses are observed. IFN-gamma+ Th1 cells from IFNgeYFP reporter mouse; comparing dnRARa to WT

2015-03-10 | E-GEOD-60354 | biostudies-arrayexpress

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