IL-36γ signaling controls the induced regulatory T cell – T(H)9 cell balance via NFκB activation and STAT transcription factors

Regulatory and effector T helper (T(H)) cells are abundant at mucosal surfaces, especially in the intestine, where they control the critical balance between tolerance and inflammation. However, the key factors that reciprocally dictate differentiation along these specific lineages remain incompletely understood. Here, we report that the interleukin (IL)-1 family member IL-36γ signals through IL-36 receptor, MyD88, and NFκBp50 in CD4(+) T cells to potently inhibit Foxp3-expressing induced regulatory T cell (T(reg)) development, while concomitantly promoting the differentiation of T helper 9 (T(H)9) cells via a IL-2-STAT5 and IL-4-STAT6 dependent pathway. Consistent with these findings, mice deficient in IL-36γ were protected from T(H) cell-driven intestinal inflammation and exhibited increased colonic T(reg) cells and diminished T(H)9 cells. Our findings thus reveal a fundamental contribution for the IL-36/IL-36R axis in regulating the T(reg)-T(H)9 cell balance with broad implications for T(H) cell-mediated disorders such as inflammatory bowel diseases, and particularly ulcerative colitis.