Suppression Of Th17 Cell Differentiation And Autoreactive Inflammatory Response By Misshapen/NIK-related Kinase MINK1

T-helper type 17(Th17)cells that produce the cytokines interleukin-17A(IL-17A)and IL-17F are major contributors to many autoimmune diseases.We demonstrate here,by using a knock-out mouse model,that the germinal center kinase family member MINKl(misshapen-like kinase 1)negatively regulates Th17 cell differentiation.The suppressive effect of MINK1 on induction of Th17 cells is mediated by the inhibition of SMAD2 activation through direct phosphorylation of SMAD2 at the T324 residue.The importance of MESK1 to Th17 cell differentiation was strengthened in animal model of experimental autoimmune encephalomyelitis(EAE),the equivalent of human multiple sclerosis,a disease critically dependent on Th17 cells.Moreover,consistent with findings that MINK 1 activity can be induced by reactive oxygen species(ROS),we show that the ROS scavenger N-acetyl cysteine boosts Th17 cell differentiation in a MINK1-dependent manner,and exacerbates the severity of EAE.Thus,we have not only established MINK1 as a critical regulator of Th17 cell differentiation,but also clarified that accumulation of ROS may limit the survival and proliferation of Th17 cells.The contribution of MINK1 to ROS-regulated Tr17 cell differentiation may suggest an important mechanism for the development of autoimmune diseases influenced by antioxidant dietary supplements.