Identify The Function And Mechanism Of REGγ In Autoimmune Disease EAE

Interleukin(IL)-17A-producing helper T(Th17)cells are a subset of CD4+ T-cells characterized by its pathological role in autoimmune diseases.Although the involvement of T cell intrinsic pathways in Thl7 cells differentiation has been well described,how instructive signals derived from the innate immune system trigger Th17 responses and inflammation remains poorly understood.Here we report that mice deficient for REGγ,a proteasome activator belongs to 11S family,showed significantly deteriorated autoimmune neuroinflammation in experimental autoimmune encephalomyelitis(EAE)model with augmented Th17 cells differentiation in vivo.Adoptive transfer of CD4+ T cells and dendritic cells(DCs)suggested that the phenomenon was driven by DCs rather than T cell intrinsic function.We next found REGγ deficiency promoted the expression of integrin αvβ8 on DCs by activating the maturation of TGF-β1 to enhance Th17 cells development.Mechanistically,this process is mediated by REGy via degradation of IRF8.Moreover,REGγ suppressed the production of IL-6 in DCs by directly controlling the stability of GSK3β to affect Th17 cells differentiation.Collectively,our results identify REGγ-mediated protein degradation as a previously unknown mechanism in DCs to control Th17 differentiation and autoimmune disease.