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The transcription factor BATF3 regulates the differentiation of TH9 cells and TH9-driven mucosal pathologies

ABSTRACT: T helper 9 (TH9) cells are important for the development of inflammatory and allergic diseases. The TH9 transcriptional network converge signals from cytokines and antigen presentation but is incompletely understood. Here, we identified TL1A, a member of the TNF superfamily, as strong inducer of mouse and human TH9 differentiation. Mechanistically, TL1A induced the expression of the transcription factors BATF and BATF3 and facilitated their binding to the Il9 promoter leading to enhanced secretion of IL-9. BATF- and BATF3-deficiencies impaired IL-9 secretion under TH9 and TH9-TL1A polarizing conditions. In vivo, using a T cell transfer model we demonstrated that TL1A promoted IL-9-dependent, TH9 cell-induced intestinal and lung inflammation. Neutralizing IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Batf3-/- TH9-TL1A cells induced reduced inflammation and cytokine expression in vivo compared to WT cells. Our results demonstrate that TL1A promotes TH9 cell differentiation and function and define a role of BATF3 in TH9-induced mucosal inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE106926 | GEO | 2019/01/08

REPOSITORIES: GEO

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TL1A signaling enhances the differentiation of TH9 cells and TH9-driven mucosal pathologies via BATF and BATF3 signaling pathways

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The TNF family member TL1A induces IL-22 secretion in committed human TH17 cells via IL-9 induction

Project description:TL1A contributes to the pathogenesis of several chronic inflammatory diseases, including Inflammatory Bowel Diseases by enhancing TH1, TH17, and TH2 responses. TL1A mediates a strong co-stimulation of these TH subsets particularly of mucosal CCR9+ T cells. However, the signaling pathways that TL1A induces in different TH subsets are incompletely understood. Here, we investigated the function of TL1A on human TH17 cells. TL1A together with TGF- IL-6, and IL-23 enhanced the secretion of IL-17 and IFN- from human CD4+ memory T cells. TL1A induced the expression of the transcription factors BATF and T-bet that correlated with the secretion of IL-17 and IFN-. In contrast, TL1A alone induced high levels of IL-22 in memory CD4+ T cells and committed TH17 cells. However, TL1A did not enhance expression of IL-17A in TH17 cells. Expression of the transcription factor aryl hydrocarbon receptor that regulates expression of IL-22 was not affected by TL1A. We performed transcriptome analysis of TH17 cells to determine genes that are transcriptionally regulated by TL1A. transcriptome analysis revealed increased expression of IL-9 in response to TL1A.

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Mus musculus

Project description:TL1A signaling enhances the differentiation of TH9 cells and TH9-driven mucosal pathologies via BATF and BATF3 signaling pathways

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The transcription factor BATF3 regulates the differentiation of TH9 cells and TH9-driven mucosal pathologies

Project description:The transcription factor BATF3 regulates the differentiation of TH9 cells and TH9-driven mucosal pathologies

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Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression

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