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 language||English (US)|
|State||Published - May 1 2018|
Bibliographical noteFunding Information:
This work was supported by NIH R01 AI106791 (BTF), P01 AI35296 (BTF), U24 U24-AI118635 (BTF), Juvenile Diabetes Research Foundation 2-2011-662 (BTF), 3-2014-215 (JAS), Regenerative Medicine of Minnesota RMM #11215 TR002 (BTF), NIH T32DK007203 (ALB), Frieda Martha Kunze Fellowship (TM), and support from anonymous donors through the University of Minnesota Foundation fund 11724 “Diabetes Cure Research Using Immune Regulation and Tolerance”. This research was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by the Juvenile Diabetes Research Foundation International (JDRF). Organ Procurement Organizations partnering with nPOD to provide research resources are listed at www.jdrfnpod.org/our-partners.php. The authors thank Dr. Alberto Pugliese, Irina Kusmartseva, and Amanda Myers for assistance procuring and preparing the human pancreas tissue sections for analysis. The authors also thank members of the University of Arizona islet isolation team: K. Smith, I. Georgiev, J. Jandova, C. Min, N. Price, D. Molano, B. Stanton, and G. Szot (UCSF).
© 2018 The Author(s).