Stat3 and Gfi-1 Transcription Factors Control Th17 Cell Immunosuppressive Activity via the Regulation of Ectonucleotidase Expression
Stat3 and Gfi-1 Transcription Factors Control Th17 Cell Immunosuppressive Activity via the Regulation of Ectonucleotidase Expression
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DOI：
10.1016/j.immuni.2011.12.019
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发表时间：
2012-03-23
期刊：
影响因子：
32.4
通讯作者：
Ghiringhelli, Francois
中科院分区：
文献类型：
--
作者：
Chalmin, Fanny;Mignot, Gregoire;Ghiringhelli, Francois
尽管Th17细胞已知可以促进组织炎症和自身免疫，但它们在癌症进展中的作用仍然难以捉摸。在这里，我们展示了在体外，用细胞因子IL-6和转化生长因子-β产生的Th17细胞表达CD39和CD73 ECTs，导致腺苷释放，随后抑制了CD4(+)和CD8(+)T细胞的效应功能。IL-6介导的转录因子STAT3的激活和转化生长因子β诱导的GFI-1转录因子的下调都是Th17细胞分化过程中胞外核苷酸酶表达所必需的。STAT3支持CD39和CD73的表达，而GFI-1通过结合CD39和CD73启动子抑制CD39和CD73的表达。相应地，经IL-1β、IL-6和IL-23分化但未经转化生长因子-β诱导的Th17细胞不表达胞外核糖核酸酶，也不具有免疫抑制作用。最后，由转化生长因子-β和IL-6诱导的Th17细胞过继转移以CD39依赖的方式促进肿瘤生长。因此，胞外核苷酸酶的表达支持Th17细胞在癌症中的免疫抑制命运。
Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-beta expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4(+) and CD8(+) T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-beta-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1 beta, IL-6, and IL-23 but without TGF-beta did not express ectonucleotidases and were not imnnunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-beta and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.