期刊
JOURNAL OF IMMUNOLOGY
卷 200, 期 10, 页码 3397-3406出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1800193
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资金
- National Institutes of Health [R01-AI053147, R01-AI109644]
- National Cancer Institute of the National Institutes of Health [P30CA33572]
T cell factor 1 (TCF-1) is expressed in both developing and mature T cells and has been shown to restrain mature T cell-mediated Th17 responses by inhibiting IL-17 expression. However, it is not clear when TCF-1 is required in vivo to restrain the magnitude of peripheral Th17 responses and what the molecular mechanisms responsible for TCF-1-regulated IL-17 gene expression are. In this study, we showed that conditional deletion of TCF-1 at the early but not later CD4(+) CD8(+) double-positive stage in mice enhanced Th17 differentiation and aggravated experimental autoimmune encephalomyelitis, which correlates with abnormally high IL-17 expression. Expression of TCF-1 in TCF-1-deficient thymocytes but not TCF-1-deficient Th17 cells inhibited IL-17 expression. TCF-1 binds to IL-17 promoter regions, and deletion of two TCF-1 binding sites relieves TCF-1-mediated inhibition of IL-17 promoter activity. Lastly, wild-type TCF-1, but not a TCF-1 mutant that has no intrinsic histone deacetylase activity, was able to inhibit IL-17 expression in TCF-1 deficient mouse thymocytes. Thus, our study demonstrates the requirement of TCF-1 in vivo at stages earlier than double-positive cells to restrain peripheral Th17 immunity by directly binding and inhibiting IL-17 promoter in its intrinsic histone deacetylase-dependent manner.
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