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KLF13 cooperates with c-Maf to regulate IL-4 expression in CD4+ T cells.

ABSTRACT: Kruppel-like factor (KLF) 13 is a transcription factor that positively regulates expression of the chemokine RANTES 3-5 d after activation of T cells. In this study, we document a key role for KLF13 in the expression of IL-4 in CD4(+) T cells. Gene expression analysis in activated T cells from Klf13(-/-) mice showed that IL-4, along with other Th2 cytokine genes, was downregulated when compared with cells from wild-type mice. The decreased levels of IL-4 were not associated with changes in expression of the Th2-inducing transcription factors GATA3 or c-Maf. Additional analysis revealed that KLF13 directly binds to IL-4 promoter regions and synergizes with c-Maf to positively regulate IL-4 expression. These results indicate that KLF13 is a positive regulator for differentiation of Th2 cells, as part of the transcriptional machinery that regulates IL-4 production in Th2 cells.

SUBMITTER: Kwon SJ

PROVIDER: S-EPMC7672653 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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KLF13 cooperates with c-Maf to regulate IL-4 expression in CD4+ T cells.

Kwon Seok Joo SJ Crespo-Barreto Juan J Zhang Wei W Wang Tianhong T Kim Dong Seok DS Krensky Alan A Clayberger Carol C

Journal of immunology (Baltimore, Md. : 1950) 20140512 12

Kruppel-like factor (KLF) 13 is a transcription factor that positively regulates expression of the chemokine RANTES 3-5 d after activation of T cells. In this study, we document a key role for KLF13 in the expression of IL-4 in CD4(+) T cells. Gene expression analysis in activated T cells from Klf13(-/-) mice showed that IL-4, along with other Th2 cytokine genes, was downregulated when compared with cells from wild-type mice. The decreased levels of IL-4 were not associated with changes in expre ...[more]

PMID: 24821970

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Project description:BackgroundCD4 + Th1 cells producing IFN-γ are required to eradicate intracellular pathogens, however if uncontrolled these cells can cause immunopathology. The cytokine IL-10 is produced by multiple immune cells including Th1 cells during infection and regulates the immune response to minimise collateral host damage. In this study we aimed to elucidate the transcriptional network of genes controlling the expression of Il10 and proinflammatory cytokines, including Ifng in Th1 cells differentiated from mouse naive CD4 + T cells.MethodsWe applied computational analysis of gene regulation derived from temporal profiling of gene expression clusters obtained from bulk RNA sequencing (RNA-seq) of flow cytometry sorted naïve CD4 + T cells from mouse spleens differentiated in vitro into Th1 effector cells with IL-12 and IL-27 to produce Ifng and Il10, compared to IL-27 alone which express Il10 only , or IL-12 alone which express Ifng and no Il10, or medium control driven-CD4 + T cells which do not express effector cytokines . Data were integrated with analysis of active genomic regions from these T cells using an assay for transposase-accessible chromatin with sequencing (ATAC)-seq, integrated with literature derived-Chromatin-immunoprecipitation (ChIP)-seq data and the RNA-seq data, to elucidate the transcriptional network of genes controlling expression of Il10 and pro-inflammatory effector genes in Th1 cells. The co-dominant role for the transcription factors, Prdm1 (encoding Blimp-1) and Maf (encoding c-Maf) , in cytokine gene regulation in Th1 cells, was confirmed using T cells obtained from mice with T-cell specific deletion of these transcription factors.ResultsWe show that the transcription factors Blimp-1 and c-Maf each have unique and common effects on cytokine gene regulation and not only co-operate to induce Il10 gene expression in IL-12 plus IL-27 differentiated mouse Th1 cells, but additionally directly negatively regulate key proinflammatory cytokines including Ifng, thus providing mechanisms for reinforcement of regulated Th1 cell responses.ConclusionsThese data show that Blimp-1 and c-Maf positively and negatively regulate a network of both unique and common anti-inflammatory and pro-inflammatory genes to reinforce a Th1 response in mice that will eradicate pathogens with minimum immunopathology.

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KLF13 cooperates with c-Maf to regulate IL-4 expression in CD4+ T cells.

Publications

KLF13 cooperates with c-Maf to regulate IL-4 expression in CD4+ T cells.

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