Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Nat Immunol. 2015 Mar;16(3):286-95. doi: 10.1038/ni.3099. Epub 2015 Feb 2.
Interleukin 17 (IL-17)-producing helper T cells (TH17 cells) and CD4(+) inducible regulatory T cells (iTreg cells) emerge from an overlapping developmental program. In the intestines, the vitamin A metabolite retinoic acid (RA) is produced at steady state and acts as an important cofactor to induce iTreg cell development while potently inhibiting TH17 cell development. Here we found that IL-1 was needed to fully override RA-mediated expression of the transcription factor Foxp3 and induce protective TH17 cell responses. By repressing expression of the negative regulator SOCS3 dependent on the transcription factor NF-κB, IL-1 increased the amplitude and duration of phosphorylation of the transcription factor STAT3 induced by TH17-polarizing cytokines, which led to an altered balance in the binding of STAT3 and STAT5 to shared consensus sequences in developing T cells. Thus, IL-1 signaling modulated STAT activation downstream of cytokine receptors differently to control the TH17 cell-iTreg cell developmental fate.
白细胞介素 17（IL-17）-产生辅助性 T 细胞（TH17 细胞）和 CD4（+）诱导性调节性 T 细胞（iTreg 细胞）来源于一个重叠的发育程序。在肠道中，维生素 A 代谢产物视黄酸（RA）在稳定状态下产生，作为诱导 iTreg 细胞发育的重要辅助因子，同时强烈抑制 TH17 细胞的发育。在这里，我们发现白细胞介素 1（IL-1）需要完全推翻 RA 介导的转录因子 Foxp3 的表达，并诱导保护性 TH17 细胞反应。通过抑制 NF-κB 依赖的转录因子 NF-κB 负调节因子 SOCS3 的表达，IL-1 增加了 TH17 极化细胞因子诱导的转录因子 STAT3 磷酸化的幅度和持续时间，从而导致发育中的 T 细胞中 STAT3 和 STAT5 与共享共识序列的结合发生改变。因此，IL-1 信号转导通过改变细胞因子受体下游的 STAT 激活来控制 TH17 细胞-iTreg 细胞的发育命运。
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