Background
Interferon gamma (IFNγ) is a proinflammatory cytokine implicated in the pathogenesis of autoimmune diseases such as type 1 diabetes (T1D). However, neutralization or genetic deficiency of IFNγ or its receptor have been disappointing in reducing disease progression and IFNγ inhibits T-cell proliferation by uncertain molecular mechanisms. We characterised islet antigen-specific T cells in non-obese diabetic (NOD) mice, a model of spontaneous T1D, lacking the three IFN receptor genes (Ifngr, Ifnar and Ifnlr). Islet antigen-specific CD8+ T cells were quantified using tetramer enrichment and flow cytometry.
Results
Diabetes developed to the same extent and at the same rate in Ifngr mutant and control NOD mice. However, at 125 days of age, antigen-specific CD8+ T cells, quantified using tetramers, were present in 10-fold greater numbers in Ifngr mutant NOD mice despite reduced inflammation. Islet-infiltrating T cells from Ifngr mutant mice had increased proliferative responses to interleukin 2 (IL-2). T cells from Ifngr mutant mice showed increased levels of phosphorylated STAT5 in response to IL-2. They also had reduced expression of phosphorylated STAT1 and its target gene, suppressor of cytokine signalling 1 (SOCS-1). Beta cells in these mice had decreased expression of PD-L1 as expected. Diabetes susceptibility was not altered in NOD mice with mutations in more than one IFN receptor. Only mice with Ifngr deficiency displayed increased antigen specific CD8+ T cells.
Conclusions
Expansion of antigen-specific CD8+ T cells is likely to explain the lack of protection from diabetes in Ifngr mutant NOD mice. We have excluded redundancy amongst the IFNs as the cause of this. IFN-γ homeostatically controls the expansion of antigen-specific CD8+ T cells by mechanisms that include increased PD-L1 expression and increased SOCS-1 expression that regulates IL-2 responsiveness. These studies indicate the importance of regulation of antigen-specific CD8+ T cells in controlling progression to type 1 diabetes.