The role of programmed death-1 in regulating islet-specific CD4 T cells

Abstract

Abstract The inhibitory receptor programmed death (PD)-1 and its ligand PD-L1 negatively regulate T cell function. PD-1 blockade is used in the clinic to reinvigorate anti-tumor immunity. However, patients often experience autoimmune-like symptoms, or develop autoimmunity, including type 1 diabetes. We used peptide:MHC Class II tetramers to track islet-specific CD4 T cells in diabetes-prone (NOD) mice and ask how PD-1 regulated this population. We found that insulin-specific cells with the highest affinity for cognate antigen expressed the most PD-1. In turn, PD-1 blockade promoted the accumulation of high-affinity cells in the pancreas, and exacerbated diabetes. Given that 70% of insulin-specific cells are anergic, we investigated whether PD-1 was required for the maintenance of anergic state, using an adoptive cell transfer model. Anergic cells remained functionally blunted in comparison to effector cells after anti-PD-L1 treatment, suggesting that anergy maintenance depends on other signaling pathways. This work highlights how the differentiation status of a T cell may predetermine its susceptibility to PD-1 blockade, and has implications for cancer immunotherapy and autoimmunity.