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Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses

ABSTRACT: Subset-specific and progenitor gene expression analysis of Klf4+/+ and Klf4-/- DCs. The two major lineages of classical dendritic cells (cDCs) express and require either IRF8 or IRF4 transcription factors for their development and function. IRF8-dependent cDCs promote anti-viral and T-helper 1 (Th1) cell responses, whereas IRF4-expressing cDCs have been implicated in controlling both Th2 and Th17 cell responses. Here, we have provided evidence that Kruppel-like factor 4 (Klf4) is required in IRF4-expressing cDCs to promote Th2 but not Th17 cell responses in vivo. Conditional Klf4 deletion within cDCs impaired Th2 cell responses during Schistosoma mansoni infection, Schistosoma egg antigen (SEA) immunization, and house dust mite challenge (HDM), without affecting cytotoxic T lymphocyte (CTL), Th1 and Th17 cell responses to herpes simplex virus, Toxoplasma gondii and Citrobacter rodentium infections. Further, Klf4 deletion reduced IRF4 expression in pre-cDCs and resulted in selective loss of IRF4-expressing cDCs subsets in several tissues. These results indicate that Klf4 guides a transcriptional program promoting IRF4-expressing cDCs heterogeneity.

ORGANISM(S): Mus musculus

PROVIDER: GSE68590 | GEO | 2015/05/19

SECONDARY ACCESSION(S): PRJNA283148

REPOSITORIES: GEO

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Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses

Project description:Subset-specific and progenitor gene expression analysis of Klf4+/+ and Klf4-/- DCs. The two major lineages of classical dendritic cells (cDCs) express and require either IRF8 or IRF4 transcription factors for their development and function. IRF8-dependent cDCs promote anti-viral and T-helper 1 (Th1) cell responses, whereas IRF4-expressing cDCs have been implicated in controlling both Th2 and Th17 cell responses. Here, we have provided evidence that Kruppel-like factor 4 (Klf4) is required in IRF4-expressing cDCs to promote Th2 but not Th17 cell responses in vivo. Conditional Klf4 deletion within cDCs impaired Th2 cell responses during Schistosoma mansoni infection, Schistosoma egg antigen (SEA) immunization, and house dust mite challenge (HDM), without affecting cytotoxic T lymphocyte (CTL), Th1 and Th17 cell responses to herpes simplex virus, Toxoplasma gondii and Citrobacter rodentium infections. Further, Klf4 deletion reduced IRF4 expression in pre-cDCs and resulted in selective loss of IRF4-expressing cDCs subsets in several tissues. These results indicate that Klf4 guides a transcriptional program promoting IRF4-expressing cDCs heterogeneity. Bone marrow progenitors and skin draining LN subsets were harvested from 4 Klf4fl/fl cre negative or Vav1-icre mice and were sorted to >95% purity on the FACS Aria 3.

2015-05-19 | E-GEOD-68590 | biostudies-arrayexpress

JunB regulates the common and lineage-specific transcriptional programs of distinct CD4+ effector T cells

Project description:IRF4 is critical for differentiation of various CD4+ effector T cells, such as T helper 1 (Th1), Th2, and Th17 subsets, through interaction with BATF-containing AP-1 heterodimers. A major BATF heterodimeric partner, JunB, regulates Th17 differentiation, but the role of JunB in other CD4+ effector T subsets is not fully understood. Here we demonstrate that JunB is essential for accumulation of Th1 and Th2 cells, as well as Th17 cells, both in vitro and in vivo. In mice immunized with lipopolysaccharide (LPS), papain, or complete Freund’s adjuvant (CFA), that induce predominantly Th1, Th2 and Th17 cells, respectively, accumulation of antigen-primed, Junb-deficient CD4+ T cells is significantly impaired. Loss of JunB decreases viability of cells activated under Th1-, Th2-, and Th17-polarizing conditions. RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) reveal that JunB directly regulates expression of various genes that are commonly induced in priming of naïve CD4+ T cells, including a pro-apoptotic gene Bcl2l11 (encoding Bim), and genes that are specifically induced in Th1, Th2, and Th17 cells. Furthermore, JunB colocalizes with BATF and IRF4 at genomic regions for approximately half of JunB direct target genes. Taken together, JunB, in collaboration with BATF and IRF4, serves a critical function in differentiation of diverse CD4+ T cells by controlling common and lineage-specific gene expression.

2021-10-01 | GSE172490 | GEO

BATF-JUN is critical for IRF4-mediated transcription in T cells

Project description:Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity, allowing IRF4 to regulate genes containing ETS–IRF composite elements (EICEs; 5'-GGAAnnGAAA-3'). Here we show that in mouse CD4+ T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1–IRF4 composite (5'-TGAnTCA/GAAA-3') motifs that we denote as AP1–IRF composite elements (AICEs). Moreover, BATF–JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4+ T cells stimulated with IL-21 and in TH17 differentiated cells. Importantly, BATF binding was diminished in Irf4-/- T cells and IRF4 binding was diminished in Batf-/- T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in TH17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription. Genome-wide transcription factors mapping and binding of IRF4, BATF, IRF8, STAT3, JUN etc in WT, Irf4-/- and Batf-/- mice in different cell types (B cells, CD4+ T cells and TH17 cells) cultured with or without IL-21 was conducted. RNA-Seq is conducted in mouse B cells, CD4+ T cells, TH1/TH2/TH9/TH17/Treg.

2012-09-18 | E-GEOD-39756 | biostudies-arrayexpress

Project Title: Proteome analysis of CD4+ T cell subsets

Project description:Functionally distinct CD4+ helper T (Th) cell subsets, such as Th1, Th2, Th17, and regulatory T cells (Treg), play a pivotal role in the host-defense against pathogen invasion and the pathogenesis of inflammatory disorders. In this project, DIA-MS-based proteome analysis was performed on naïve CD4+ T, Th0, Th1, Th2, Th17 and iTreg cells using Q Exactive HF-X (Thermo Fisher Scientific) to search for proteins that differ among the cell subsets.

2023-01-04 | PXD036065 | JPOST Repository

Transcriptional profiles of CCR7lo effector memory human T cell subsets

Project description:The aim of this study was to identify differentially-expressed genes in CCR4hi/CXCR3- and CCR4lo CXCR3+ CCR6+ human Th17 cell subsets Human CD45RO+ memory T cells isolated from the peripheral blood of healthy adult donors were sorted into 4 predominant CCR7lo CD25- effector memory subsets: (1) Th1 - CCR6- CCR4lo CXCR3+; (2) Th2 - CCR6- CCR4hi CXCR3+; (3) Th17 - CCR6+ CCR4hi CXCR3-; (4) Th17.1 - CCR6+ CCR4lo CXCR3-. Sorted cells were cultured in media and activated via anti-CD3/anti-CD28 beads for 36 hours. All subsets were then harvested and used for RNA extraction and microarray experiments. Th1 vs Th2; Th1 vs Th17; Th1 vs Th17.1; Th2 vs Th17; Th2 vs Th17.1; Th17 vs Th17.1

2013-12-17 | E-GEOD-49703 | biostudies-arrayexpress

Distinct populations of CD11b+ IRF4+ dendritic cells drive Th2 responses in the small intestine and colon

Project description:We have identified the dendritic cell (DC) populations that are sufficient for the induction of T helper 2 (Th2) cell responses in the intestine against both live Trichuris muris worms, and inert Schistosoma mansoni eggs. Antigen-specific Th2 responses did not develop after deletion of IRF4 in DCs, yet IRF4-deficient DCs were not functionally affected. Instead, IRF4flox/flox CD11c-cre mice had fewer CD11b+ migrating DCs, and fewer DCs carrying parasite antigen from the intestine. Adoptive transfer of purified DCs from infected animals directly into intestinal afferent lymphatics enabled us to identify that CD11b+CD103+ DCs were central to the induction of Th2 responses in the small intestine, whereas CD11b+CD103- DCs were more important in the colon. Similarly, after pulsing with Schistosome egg antigen (SEA) in vitro, adoptively-transferred small intestinal or colonic DCs acquired the ability to induce SEA-specific Th2 responses. These data demonstrate a functional specialisation among intestinal DC populations in inducing Th2 responses, and elucidate the roles of IRF4 in this process.

2016-12-10 | GSE91381 | GEO

General Anesthesia Combined With Epidural Anesthesia Mitigates the Surgical Stress-related Immunosuppression in Patients With Colorectal Cancer

Project description:The purpose of this study is to prove whether general anesthesia combined with epidural anesthesia could better maintain body balance of Th1/Th2 and Treg/Th17 compared with general anesthesia, so as to reduce the surgical stress-related immunosuppression, and to improve the prognosis.

| 2154377 | ecrin-mdr-crc

TIGIT+ Tregs

Project description:TIGIT+ Tregs suppress Th1 and Th17 responses while sparing Th2 responses. Analysis of global gene expression of TIGIT+ vs. TIGIT- Tregs from naive mice reveled that TIGIT+ Tregs display an activated phenotype and are enriched for Treg signature genes including the Treg effector molecule Fgl2 which enables them to selectively spare Th2 responses.

2014-12-12 | GSE56299 | GEO

Lipidomic analysis of CD4+ T-cell subsets (Th1,Th2,Th17 and iTreg cells) (part I)

Project description:Part 1/5: It includes lipidomic analysis of CD4+ T-cell subsets(Th1,Th2,Th17 and iTreg cells)and their paired controls(Th0 cells).

2021-01-28 | ST001676 | MetabolomicsWorkbench

TIGIT+ Tregs

2014-12-12 | E-GEOD-56299 | biostudies-arrayexpress

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