The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice

TLDR

Programmed death‑1 (PD‑1) is an inhibitory costimulatory receptor on activated T cells that regulates immune responses and peripheral tolerance. The study examined the role of the PD‑1 pathway in the onset of autoimmune diabetes. Blockade of PD‑1 or PD‑L1 rapidly induced diabetes in pre‑diabetic NOD mice of all ages, especially older females, while CTLA‑4 blockade only triggered disease in neonates; male NOD mice also succumbed to PD‑1/PD‑L1 blockade but resistant NOR mice did not, and the treatment increased insulitis, IFN‑γ–producing GAD‑reactive splenocytes, and revealed PD‑L1 expression on inflamed islets, underscoring the central role of PD‑1/PD‑L1 in autoimmune diabetes and motivating therapeutic targeting of this pathway.

Abstract

Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon γ–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.