IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the T(H)17 cell-iT(reg) cell balance

摘要

Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) and CD4(+) inducible regulatory T cells (iT(reg) 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 iT(reg) cell development while potently inhibiting T(H)17 cell development. Here we found that IL-1 was needed to fully override RA-mediated expression of the transcription factor Foxp3 and induce protective T(H)17 cell responses. By repressing expression of the negative regulator SOCS3 dependent on the transcription factor NF-kappa B, IL-1 increased the amplitude and duration of phosphorylation of the transcription factor STAT3 induced by T(H)17-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 T(H)17 cell-iT(reg) cell developmental fate.