Interferons limit autoantigen-specific CD8+ T-cell expansion in the non-obese diabetic mouse

Interferon gamma (IFNg) is a proinflammatory cytokine implicated in autoimmune diseases. However, deficiency or neutralization of IFNg have been disappointing in reducing disease. We characterised islet antigen-specific T cells in non-obese diabetic (NOD) mice lacking all three IFN receptor genes. Diabetes was minimally affected, however, at 125 days of age antigen-specific CD8+ T cells, quantified using major histocompatibility complex class I tetramers, were present in 10-fold greater numbers in Ifngr mutant NOD mice. T cells from Ifngr mutant mice had increased proliferative responses to interleukin 2 (IL-2). They also had reduced phosphorylated STAT1 and its target gene, suppressor of cytokine signalling 1 (SOCS-1). IFN-g controls the expansion of antigen-specific CD8+ T cells by mechanisms that include increased SOCS-1 expression that regulates IL-2 signaling. The expanded CD8+ T cells are likely to contribute to normal diabetes progression despite reduced inflammation in Ifngr mutant mice. Overall design: Bulk TCRßseq of IGRP-tetramer positive CD8 T cells and non-tetramer CD8+CD44+ T cells sorted from peripheral lymphoid organs (PLO) of 4 wild-type NOD mice and 4 Ifngr1-mutant NOD mice at 125 days of age. Each sample represents an individual biological replicate (i.e. no duplicate samples from the same mouse).