期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 9, 页码 1807-1819出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20131548
关键词
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资金
- Deutsche Forschungsgemeinschaft [SFB 633]
- German Federal Ministry of Education and Research (BMBF) [01GU0721]
- ERC Advanced Grant [ERC-2010-AdG_20100317, 268987]
- e:Bio - Innovationswettbewerb Systembiologie program of the Federal Ministry of Education
Secretion of the immunosuppressive cytokine interleukin (IL) 10 by effector T cells is an essential mechanism of self-limitation during infection. However, the transcriptional regulation of IL-10 expression in proinflammatory T helper (Th) 1 cells is insufficiently understood. We report a crucial role for the transcriptional regulator Blimp-1, induced by IL-12 in a STAT4-dependent manner, in controlling IL-10 expression in Th1 cells. Blimp-1 deficiency led to excessive inflammation during Toxoplasma gondii infection with increased mortality. IL-10 production from Th1 cells was strictly dependent on Blimp-1 but was further enhanced by the synergistic function of c-Maf, a transcriptional regulator of IL-10 induced by multiple factors, such as the Notch pathway. We found Blimp-1 expression, which was also broadly induced by IL-27 in effector T cells, to be antagonized by transforming growth factor (TGF) beta. While effectively blocking IL-10 production from Th1 cells, TGF-beta shifted IL-10 regulation from a Blimp-1-dependent to a Blimp-1-independent pathway in IL-27-induced Tr1 (T regulatory 1) cells. Our findings further illustrate how IL-10 regulation in Th cells relies on several transcriptional programs that integrate various signals from the environment to fine-tune expression of this critical immunosuppressive cytokine.
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