Interferon-gamma drives programmed death-ligand 1 expression on islet \u03b2 cells to limit T cell function during autoimmune diabetes

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

doi:10.1038/s41598-018-26471-9

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.

Highlights

The inhibitory receptor Programmed Death-1 (PD-1) and its ligands Programmed Death Ligand (PD-L) 1 and 2 are critical regulators of immune cell function and autoimmunity[1,2,3,4,5,6,7]
In non-obese diabetic (NOD) mice, β cells were identified as side and forward scatter high, CD45.1 negative, CD4 negative, lineage marker negative (CD8−, CD11c−, CD11b−, B220−, F4/80−), live cells, that were positive for intracellular insulin (Fig. 1)
We measured an increase in the level of programmed death ligand-1 (PD-L1) expression on β cells as determined by the geometric mean fluorescent intensity on β cells from diabetic mice compared to all other ages except for 5 week old NOD mice (Fig. 2D)

Summary

Introduction

The inhibitory receptor Programmed Death-1 (PD-1) and its ligands Programmed Death Ligand (PD-L) 1 and 2 are critical regulators of immune cell function and autoimmunity[1,2,3,4,5,6,7]. Single nucleotide polymorphisms in the PDCD1 or CD274 genes have been associated with T1D16–18 Adverse events such as rapid autoimmunity including T1D can develop following checkpoint blockade in cancer patients[19,20], further suggesting a role for this inhibitory pathway in autoimmunity. Previous work suggests that PD-1:PD-L1 interactions within the pancreas may limit autoimmune diabetes[6,8,26] Despite this body of knowledge, the timing, location, and specific cellular interactions that are regulated by PD-1:PD-L1 in T1D remain unclear. While previous reports have shown intra-islet PD-L1 expression on infiltrating mononuclear cells[6,27], and suggest a role for non-hematopoietic PD-L1 expression to limit diabetes, it is unclear if β cells themselves express PD-L1 and how this expression is regulated during diabetes progression. This work illustrates that both mouse and human islet β cells express PD-L1 in response to the same inflammatory cues, which may help delay islet destruction, but is insufficient to prevent β cell death

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