A Critical Role for NKG2D Signaling in beta cell-specific CTL Generation and NOD Diabetes 2257932

Abstract

Abstract Introduction Type 1 diabetes (T1D) is an autoimmune disorder caused by T cell-mediated destruction of pancreatic β cells. There is a critical need to develop novel therapies for this disease, which requires further understanding of T1D pathogenesis. One pathway that is implicated is signaling through the immune receptor NKG2D. However, NKG2D’s role has remained unclear due to conflicting reports in the literature. Methods We generated multiple novel mouse strains on the non-obese diabetic (NOD) background to better define the role of NKG2D in autoimmune diabetes. We compared diabetes incidence, insulitis, including digital spatial profiling, and islet-specific CD8+ CTL generation between mice genetically deficient in NKG2D (NKG2D KO) and wild-type (WT) mice housed in both specific-pathogen-free (SPF) and germ-free (GF) conditions. Results NKG2D KO mice had delayed diabetes, insulitis, and CD8+ T cell pancreatic infiltration, with the most significant effect in GF and male mice. Further, we found that NKG2D signaling did not occur in the pancreas, that NKG2D ligands were expressed in the pancreatic lymph node, that deletion of NKG2D in CD8+ T cells was required to delay diabetes, that there was reduced differentiation of CTL from islet-specific naive NKG2D KO CD8+ T cells, and that the transcriptome of NKG2D KO CTL was altered. Additionally, we found that blocking NKG2D signaling similarly reduced human CTL differentiation. Conclusion The results of our studies definitively demonstrate that NKG2D in CD8+ T cells plays a critical role in autoimmune diabetes. We show this role is to enhance CTL generation rather than the CTL effector response in islets as previously proposed. Further, our data explain the conflicting reports surrounding NKG2D’s role, as we reveal the existence of redundant, compensatory signaling that is influenced by the microbiome and sex. This inherent redundancy strongly suggests that signaling through NKG2D or its compensatory pathway is critical for islet-specific CTL generation. Funding Source Breakthrough T1D (3-SRA-2023-1412-S-B and 1-INO-2022-1118-A-N), NIH P20GM104936 Topic Categories Basic Autoimmunity (BA)