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The AP-1 Transcription Factor JunB Is Required for Th17 Cell Differentiation

ABSTRACT: Interleukin (IL)-17-producing T helper (Th17) cells are crucial for host defense against extracellular microbes and pathogenesis of autoimmune diseases. Here we show that the AP-1 transcription factor JunB is required for Th17 cell development. Junb-deficient CD4+ T cells are able to develop in vitro into various helper T subsets except Th17. The RNA-seq transcriptome analysis reveals that JunB is crucial for the Th17-specific gene expression program. Junb-deficient mice are completely resistant to experimental autoimmune encephalomyelitis, a Th17-mediated inflammatory disease, and naive T helper cells from such mice fail to differentiate into Th17 cells. JunB appears to activate Th17 signature genes by forming a heterodimer with BATF, another AP-1 factor essential for Th17 differentiation. The mechanism whereby JunB controls Th17 cell development likely involves activation of the genes for the Th17 lineage-specifying orphan receptors RORt and ROR and reduced expression of Foxp3, a transcription factor known to antagonize RORt function.

ORGANISM(S): Mus musculus

PROVIDER: GSE98242 | GEO | 2018/02/15

REPOSITORIES: GEO

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JunB plays a crucial role in the development of regulatory T cells by regulating interleukin-2 signaling

Project description:The AP-1 transcription factor JunB is crucial for multiple biological processes, such as placental development and bone homeostasis. We recently reported that JunB plays an essential role in development of Th17 cells, and thus Junb-deficient mice are resistant to experimental autoimmune encephalomyelitis. However, the role of JunB in CD4+ T cells under other inflammatory disease conditions is unknown. Here we show that mice lacking JunB in CD4+ T cells (Junbfl/flCd4-Cre mice) were more susceptible to dextran sulfate sodium (DSS)-induced colitis, a disease model induced by innate immune cells. While the Th17-associated genes Il17a and Il22 are shown to be protective against DSS-induced colitis, their expression was not impaired in the colon of Junbfl/flCd4-Cre mice. In addition to the defect in Th17 development, the colon of Junbfl/flCd4-Cre mice exhibited reduction in regulatory T (Treg) cells. Junb-deficient CD4+ T cells needed high concentration of IL-2 for differentiating into Treg cells in vitro because of their hyporesponsiveness to IL-2. Mechanistically, JunB directly up-regulated expression of CD25, the α−chain of high affinity IL-2 receptor, thereby increasing a sensitivity to IL-2 under Treg-inducing conditions. We uncover a crucial role for JunB in development of Treg cells and defense against an epithelial cell damage-induced colitis.

2020-03-31 | GSE120814 | GEO

JunB plays a crucial role in the development of regulatory T cells by increasing a sensitivity to interleukin-2

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Chemical Inhibition of the ROR?t-dependent Transcriptional Network in Th17 cells [RNA-Seq]

Project description:ROR?t is a transcription factor required for T helper 17 (Th17) cell development. We identified three ROR?t-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized ROR?t binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and ROR?t-deficient cells. ROR?t is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced ROR?t from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. Transcriptional profiling of Th17 cells under chemical perturbations of ROR?t, DMSO, and knockout of ROR?t

2014-04-17 | E-GEOD-56018 | biostudies-arrayexpress

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Project description:Here we identify the activator protein-1 (AP-1) factor JunB as an essential regulator of Th17 cell identity. JunB activates the expression of Th17 lineage-specifying genes, and coordinately represses genes controlling Th1 and Treg fate. Through regulatory analysis, we find that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T cell potential.

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Role of JunB in Th17 cell effector stability [ChIP-seq]

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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.

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JunB is essential for IL-23-dependent pathogenicity of Th17 cells.

Project description:To understand molecular mechanisms by which JunB regulates Th17 differentiation, we performed microarray analyses of JunB-deficient and control Th17 cells.

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JunB is essential for IL-23-dependent pathogenicity of Th17 cells.

Project description:To understand molecular mechanisms by which JunB regulates Th17 differentiation, we performed ChIP-seq analyses of JunB-deficient and control Th17 cells.

2017-04-11 | GSE86535 | GEO

Global miRNA expression profiling of Junb-deficient murine embryonic fibroblasts

Project description:The AP-1 transcription factor subunit Junb acts as a context-dependent transcriptional regulator. While positive regulatory functions of Junb are widely studied, the mechanism by which Junb exerts negative regulatory functions remains unclear. miRNAs could translate repressor functions of Junb. Therefore, the aim of this study was to identify Junb-dependent miRNAs in immortalized fibroblasts (MEFs) derived from murine Junb knock-out and wildtype embryos. Cells were published previously in Licht et al. (2010) J Clin Invest. 120(7):2307-18.

2015-10-13 | GSE43380 | GEO

JunB-dependent expression in colonic and Peyer's patch regulatory T cells

Project description:Foxp3-expressing regulatory T (Treg) cells are critical mediators of immunological tolerance to both self and microbial antigens. Tregs activate context-dependent transcriptional programs to adapt effector function to specific tissues; however, the factors controlling tissue-specific gene expression in Tregs remain unclear. Here, we find that the AP-1 transcription factor JunB regulates the intestinal adaptation of Tregs by controlling select gene expression programs in multiple Treg subsets. Treg-specific ablation of JunB results in immune dysregulation characterized by enhanced colonic T helper cell accumulation and cytokine production. However, in contrast to its classical binding-partner BATF, JunB is dispensable for maintenance of effector Tregs as well as most specialized Treg subsets. In the Peyer’s patches, JunB activates a transcriptional program facilitating the maintenance of CD25- Tregs, leading to the complete loss of T follicular regulatory cells in the absence of JunB. This defect is compounded by loss of a separate effector program found in both major colonic Treg subsets that includes the cytolytic effector molecule granzyme B. Therefore, JunB is an essential regulator of intestinal Treg effector function through pleiotropic effects on gene expression.

2020-02-26 | GSE145888 | GEO

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