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

Kevin C. Osum, Adam L. Burrack, Tijana Martinov, Nathanael L. Sahli, Jason S. Mitchell, Christopher G. Tucker, Kristen E. Pauken, Klearchos Papas, Balamurugan Appakalai, Justin A. Spanier, Brian T. Fife

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Type 1 diabetes is caused by autoreactive T cell-mediated β cell destruction. Even though co-inhibitory receptor programmed death-1 (PD-1) restrains autoimmunity, the expression and regulation of its cognate ligands on β cell remains unknown. Here, we interrogated β 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+ β cells as non-obese diabetic (NOD) mice aged and developed diabetes. Increased β cell PD-L1 expression was dependent on T cell infiltration, as β cells from Rag1-deficient mice lacked PD-L1. Using Rag1-deficient NOD mouse islets, we determined that IFN-γ promotes β cell PD-L1 expression. We performed analogous experiments using human samples, and found a significant increase in β 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, β cell PD-L1 expression correlated with insulitis. In vitro experiments with human islets from non-diabetic individuals showed that IFN-γ promoted β cell PD-L1 expression. These results suggest that insulin-producing β cells respond to pancreatic inflammation and IFN-γ production by upregulating PD-L1 expression to limit self-reactive T cells.

Original languageEnglish (US)
Article number26471
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - May 1 2018

ASJC Scopus subject areas

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    Osum, K. C., Burrack, A. L., Martinov, T., Sahli, N. L., Mitchell, J. S., Tucker, C. G., Pauken, K. E., Papas, K., Appakalai, B., Spanier, J. A., & Fife, B. T. (2018). Interferon-gamma drives programmed death-ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes. Scientific reports, 8(1), [26471]. https://doi.org/10.1038/s41598-018-26471-9