Type 1 diabetes is an autoimmune disease in which the pancreatic β islet cells are destroyed. The main drivers of type 1 diabetes are islet-specific T cells. These cells must escape a myriad of tolerance mechanisms that control their activation in healthy individuals. Understanding these mechanisms is critical to developing better strategies to inhibit the disease. One pathway implicated in this process is NKG2D signaling. However, the importance of NKG2D to diabetes pathogenesis is unclear owing to conflicting results from studies in which NKG2D signaling was inhibited globally. Our previous studies indicate that these inconsistent findings are due to differential effects of NKG2D signaling in response to islet antigen and the microbiota. Therefore, new experimental approaches are required to determine the roles of NKG2D during diabetes development. To this end, we generated two novel mouse models. These are transgenic NOD mice that have enhanced NKG2D ligand expression in β cells (RIP-RAE1ε mice), and NOD mice lacking expression of the NKG2D ligand endogenously expressed in islets, H60a. We found that the RIP-RAE1ε mice and H60a-deficient mice had decreased and increased diabetes, respectively. These data demonstrate that increasing NKG2D signaling within the pancreas protects, whereas eliminating NKG2D signaling enhances, NOD diabetes. Further, we show that the NKG2D-mediated protection is associated with an increase in CD8+ central memory T cells (Tcm) in vivo, which correlates with NKG2D signaling-induced generation of both mouse and human CD8+ central memory T cells in vitro, and that CD8+ Tcm protect against diabetes in the NOD.SCID adoptive transfer model. Taken together, these data indicate that NKG2D signaling protects against diabetes by enhancing the generation of a protective CD8+ Tcm population.
A. Trembath: None. N. Sharma: None. I.C. Gerling: None. C.E. Mathews: None. M.A. Markiewicz: Consultant; Self; Johnson & Johnson.
American Diabetes Association (1-12-JF-41 to M.A.M.); National Institutes of Health (P30GM103326, P30CA168524, UC4DK104167, UC4DK104155, U54HD090216, P30DK020579, P30GM122731); JDRF (5-SRA-2018-557-Q-R, 17-2012-595); The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D053); American Association of Immunologists