T cell-intrinsic ASC critically promotes Th17-mediated experimental autoimmune encephalomyelitis.

Abstract

Abstract In the present study, we uncovered a novel T cell-intrinsic role of the inflammasome adaptor molecule ASC in Th17-mediated EAE pathogenesis. We found that while T cell-intrinsic ASC is required for the effector stage of active EAE, ASC deficiency in T cells specifically impaired Th17- but not Th1-mediated passive EAE. T cells deficient in IL-1β were similarly impaired in their ability to mediate the effector phase of EAE. Mechanistically, TCR signaling induced pro-IL-1β expression and licensed T cells for inflammasome activation. Polarized Th17 cells expressed IL-1R, and produced mature IL-1β in response to ATP via ASC/NLRP3-dependent caspase-8 activation. Additionally, ATP-treated Th17 cells showed enhanced survival compared to ATP-treated Th1 cells, which was abrogated by IL-1Ra, suggesting an autocrine action of Th17-derived IL-1β. Together, these data suggest a critical role for IL-1β produced by a novel Th17 cell-intrinsic ASC-NLRP3-Caspase-8 inflammasome during CNS inflammation.