Interferon-gamma drives programmed death-ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes

Type 1 diabetes is caused by autoreactive T cell-mediated beta cell destruction. Even though co-inhibitory receptor programmed death-1 (PD-1) restrains autoimmunity, the expression and regulation of its cognate ligands on beta cell remains unknown. Here, we interrogated beta cell-intrinsic programmed death ligand-1 (PD-L1) expression in mouse and human islets. We measured a significant increase in the level of PD-L1 surface expression and the frequency of PD-L1+beta cells as non-obese diabetic (NOD) mice aged and developed diabetes. Increased beta cell PD-L1 expression was dependent on T cell infiltration, as beta cells from Rag1-deficient mice lacked PD-L1. Using Rag1-deficient NOD mouse islets, we determined that IFN-gamma promotes beta cell PD-L1 expression. We performed analogous experiments using human samples, and found a significant increase in beta cell PD-L1 expression in type 1 diabetic samples compared to type 2 diabetic, autoantibody positive, and non-diabetic samples. Among type 1 diabetic samples, beta cell PD-L1 expression correlated with insulitis. In vitro experiments with human islets from nondiabetic individuals showed that IFN-gamma promoted beta cell PD-L1 expression. These results suggest that insulin-producing beta cells respond to pancreatic inflammation and IFN-gamma roduction by upregulating PD-L1 expression to limit self-reactive T cells.NIH [R01 AI106791, P01 AI35296, U24 U24-AI118635, T32DK007203]; Juvenile Diabetes Research Foundation [2-2011-662, 3-2014-215]; Regenerative Medicine of Minnesota RMM [11215 TR002]; Frieda Martha Kunze Fellowship; University of Minnesota Foundation [11724]; Network for Pancreatic Organ Donors with Diabetes (nPOD); Juvenile Diabetes Research Foundation International (JDRF)Open access journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu