290-OR: Diabetes Progression in IFG-Receptor Deficient NOD Mice Is Associated with Increased CD8+ T Lymphocyte Sensitivity to Common Gamma Chain Cytokines

Abstract

IFN-γ is a potential drug target in type 1 diabetes and this is part of the rationale for trialing JAK inhibitors (JAKi) for treatment of new onset T1D. It regulates migration and adhesion of leucocytes, as well as expression of MHC class I on islet beta cells. However, neither genetic deficiency of IFN-γ nor its receptor in NOD mice modifies disease progression. To understand this paradox we characterised islet antigen-specific T cells in NOD mice lacking the IFN-γ receptor (Ifngr) generated directly in NOD mouse embryos using CRISPR/Cas9 gene editing. Islet antigen-specific CD8+ T cells (proinsulin B15-23 and IGRP206-214) and CD4+ T cells (proinsulin B10-23and BDC2.5 mimotope) were quantified using tetramer enrichment and flow cytometry. At 125 days of age, insulin-specific (177±41 cells in wild type and 1799±1123 cells in Ifngr mutant, p=0.036) and IGRP-specific CD8+ T cells (2524±735 cells in wild type and 30598±10426 cells in Ifngr mutant, p<0.0001) were present in significantly greater numbers in Ifngr mutant NOD mice. There were no differences in antigen-specific CD4+ T cells. Islet infiltrating T cells from Ifngr mutant mice had increased responses to common gamma chain (γc) cytokines, prevented by a JAKi, and reduced expression of suppressor of cytokine signalling-1 (Socs1) mRNA. Our data suggest that as well as its pro-inflammatory effects, IFN-γ homeostatically controls the expansion of antigen-specific CD8+ T cells by regulating their response to γc cytokines, by mechanisms that include regulation of SOCS-1 expression. Expansion of antigen-specific CD8+ T cells is likely to explain the lack of protection from diabetes in Ifngr mutant NOD mice. JAKi therapy experimentally controlled this increased responsiveness to γc cytokines. Our data show mechanisms underlying protection from diabetes in NOD mice by JAKi and the lack of protection by blocking IFN-γ alone. Disclosure T. Kay: None. G. Jhala: None. B. Krishnamurthy: None. H.E. Thomas: None.