Tyk2-mediated signaling promotes the development of autoreactive CD8+ CTLs and autoimmune type 1 diabetes

Abstract

Tyrosine kinase 2 (TYK2), a member of the JAK family, might be a susceptibility gene for type 1 diabetes (T1D), whereas its precise role in autoimmune T1D remains unknown. We showed Tyk2 deficiency and inhibition suppressed autoimmune T1D development in non-obese diabetic (NOD) mice. Defective IL-12 signaling due to Tyk2 deficiency in islet-autoreactive CD8+ CTLs during their priming reduced T-bet expression, leading to impaired Cxcr3 expression and effector functions against {beta}-cells. Tyk2 deficient CD8+ resident dendritic cells (rDC) exhibited reduced MHC I expression and impaired cross-priming of CTLs. In {beta}-cells, increased expressions of Fas, MHC I, and chemokines with age were attenuated by Tyk2 deficiency. We demonstrated that treatment with BMS-986165, a Tyk2 inhibitor, inhibited the development of CTLs and inflammation in {beta}-cells in vitro. BMS-986165 reduced the incidence of diabetes in NOD mice. Thus, we demonstrated that Tyk2-mediated signaling has a critical role in the development of autoreactive CD8+ CTLs, inflammation in {beta}-cells, and the pathogenesis of autoimmune T1D. SummaryWe demonstrated that Tyk2-mediated signaling plays a critical role in the development of autoreactive CD8+ CTLs, inflammation in {beta}-cells, and the pathogenesis of autoimmune T1D. These findings will lead to the development of safety and effective prevention strategies for T1D.