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

Interleukin 17 (IL-17)-producing helper T cells (T sub(H)17 cells) and CD4 super(+) inducible regulatory T cells (iT sub(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 sub(reg) cell development while potently inhibiting T sub(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 sub(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 sub(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 sub(H)17 cell-iT sub(reg) cell developmental fate.