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REG controls Th17 cell differentiation and autoimmune inflammation by regulating dendritic cells

Zhou, L;Yao, L;Zhang, Q;Xie, W;Wang, X;Zhang, H;Xu, J;Lin, Q;Li, Q;Xuan, Y;Ji, L;Wang, L;Wang, W;Wang, W;Shi, T;Fang, L;Zheng, B;Li, L;Liu, S;Zhang, B;Li, X;

Interleukin-17A (IL-17A)-producing helper T (Th17) cells are a subset of CD4+ T cells that play important pathological roles in autoimmune diseases. Although the intrinsic pathways of Th17 cell differentiation have been well described, how instructive signals derived from the innate immune system trigger the Th17 response and inflammation remains poorly understood. Here, we report that mice deficient in REG, a proteasome activator belonging to the 11S family, exhibit significantly deteriorated autoimmune neuroinflammation in an experimental autoimmune encephalomyelitis (EAE) model with augmented Th17 cell polarization in vivo. The results of the adoptive transfer of CD4+ T cells or dendritic cells (DCs) suggest that this phenotype is driven by DCs rather than T cells. Furthermore, REG deficiency promotes the expression of integrin v8 on DCs, which activates the maturation of TGF-1 to enhance Th17 cell development. Mechanistically, this process is mediated by the REG-proteasome-dependent degradation of IRF8, a transcription factor for v8. Collectively, our findings delineate a previously unknown mechanism by which REG-mediated protein degradation in DCs controls the differentiation of Th17 cells and the onset of an experimental autoimmune disease.