The cellular basis of the PD-1/PD-L1 regulatory pathway in diabetic autoimmunity in the NOD mouse

Abstract

Abstract We report our studies on the effects of checkpoint blockade on the development of diabetic autoimmunity in the NOD mouse. One of the complications of checkpoint blockade therapy in cancer patients is the development of acute type 1 diabetes (T1D). We confirm that the PD-1/PD-L1 regulatory pathway is highly involved in T1D in the NOD mouse. In NOD autoimmunity there is an entry of CD4+ T cells specific to insulin peptides shortly after weaning followed by CD103+ dendritic cells (DC), CD4+ T cells and CD8+ T cells recognizing broader islet antigens into the pancreatic islets. The islet resident macrophages and infiltrated DCs, as well as the endothelium and the beta cells, express PD-L1. Diabetes doesn’t develop in NOD mice until about 20 weeks of age or later. Administration of anti-PD-1 antibody rapidly induces diabetes in the young mice showing a control phase established very early in the autoimmune process. Anti-PD-1 treatment induces a high level of islet leukocytes infiltration including CD4+ T cells and CD8+ T cells. The regulatory effect of PD-1 is involved in both CD4+ T cells which recognize self-peptides via H2g7MHC haplotype, as well as in CD8+ T cells. The islet resident macrophage is an essential component for the PD-1/PD-L1 regulatory pathway to take effect. In their absence, no diabetes develops even after anti-PD-1 treatment. The same observation is found in the NOD.Batf-3−/− mice. We suggest that the control mechanism takes place once T cells enter islets. To establish PD-1 regulation, IFNγ signaling is required probably via up-regulating PD-L1 expression on various types of cells in islets. Together, our study has explored the cellular basis of PD-1 in regulating diabetic autoimmunity in the NOD mouse.