NKG2D signaling in CD8+ T cell differentiation and diabetes 4195

Abstract Description Type 1 diabetes is an autoimmune disease in which CD8+ T cells play a pivotal role in β-cell destruction through cytotoxic activity. This study aimed to determine the importance of NKG2D signaling during CD8+ cytotoxic T lymphocyte (CTL) differentiation in T1D pathogenesis in mouse and human models. We compared diabetes development and NKG2D ligand expression in non-obese diabetic (NOD) mice for NKG2D WT and KO housed under specific pathogen free (SPF) and germ-free conditions. We assessed islet antigen-specific CTL effector function and mRNA expression in the WT and KO after activation with APCs. Additionally, the immune cell infiltrate in NKG2D WT and KO NOD islets was compared using proteomic spatial profiling. Our data show that NKG2D signaling exacerbates NOD diabetes. NKG2D KO significantly reduced diabetes incidence in NOD mice, particularly in males as compared to females and those housed in a germ-free environment. APCs from SPF conditions showed higher cytokine production than those from germ-free. NKG2D signaling in human CTLs also increased cytokine production. Our data showed that male NKG2D KO mice displayed reduced CD45 expression and increased expression of the exhaustion marker Tim-3. Male NKG2D KO mice exhibit reduced CD8+ CTLs in islets, which we hypothesize leads to T cell exhaustion. NKG2D signaling has the greatest effect under germ-free conditions and in males, suggesting an alternative signal compensates for NKG2D’s function in inverse scenario. Funding Sources Breakthrough T1D: 3-SRA-2023-1412-S-B DOD: HT9425-23-1-0630 Emilie Rosebud Diabetes Research Foundation (no number) University of Kansas Diabetes Institute (no number) American Diabetes Association: 1-12-JF-41 American Association of Immunologists (no number) NIH/NIGMS: P20GM104936 Topic Categories Basic Autoimmunity (BA)