BATF2 prevents T-cell-mediated intestinal inflammation through regulation of the IL-23/IL-17 pathway
BATF2 prevents T-cell-mediated intestinal inflammation through regulation of the IL-23/IL-17 pathway
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DOI：
10.1093/intimm/dxz014
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发表时间：
2019-06-01
影响因子：
4.4
通讯作者：
Takeda, Kiyoshi
中科院分区：
文献类型：
--
作者：
Kayama, Hisako;Tani, Haruka;Takeda, Kiyoshi
Inappropriate activation of the IL-23 signaling pathway causes chronic inflammation through the induction of immunopathological T(h)17 cells in several tissues including the intestine, whereas adequate T(h)17 responses are essential for host defense against harmful organisms. In the intestinal lamina propria, IL-23 is primarily produced by innate myeloid cells including dendritic cells (DCs) and macrophages (Ms). However, the molecular mechanisms underlying the regulation of IL-23 production by these cells remains poorly understood. In this study, we demonstrated that BATF2 regulates intestinal homeostasis by inhibiting IL-23-driven T-cell responses. Batf2 was highly expressed in intestinal innate myeloid subsets, such as monocytes, CD11b(+) CD64(+) M phi s and CD103(+) DCs. Batf2(-/-) mice spontaneously developed colitis and ileitis with altered microbiota composition. In this context, IL-23, but not TNF-alpha and IL-10, was produced in high quantities by intestinal CD11b(+) CD64(+) M phi s from Batf2(-/-) mice compared with wild-type mice. Moreover, increased numbers of IFN-(+), IL-17(+) and IFN-(+) IL-17(+) CD4(+) T cells, but not IL-10(+) CD4(+) T cells, accumulated in the colons and small intestines of Batf2(-/-) mice. In addition, RORt-expressing innate lymphoid cells were increased in Batf2(-/-) mice. Batf2(-/-)Rag2(-/-) mice showed a reduction in intestinal inflammation present in Batf2(-/-) mice. Furthermore, the high numbers of intestinal IL-17(+) and IFN-(+) IL-17(+) CD4(+) T cells were markedly reduced in Batf2(-/-) mice when introducing Il23a deficiency, which was associated with the abrogation of intestinal inflammation. These results indicated that BATF2 in innate myeloid cells is a key molecule for the suppression of IL-23/IL-17 pathway-mediated adaptive intestinal pathology.
