Identification of self-specific CD4+ T cell subsets resistant to PD-1 blockade (BA11P.130)

Abstract

Abstract The inhibitory receptor programmed death (PD)-1 and its ligand PD-L1 regulate T cell function to limit autoimmunity. PD-1 is highly expressed on exhausted T cells, limiting their antiviral or antitumor activity. Even though PD-1 pathway blockade has gained momentum in cancer treatment, it is unclear how PD-1/PD-L1 blockade impacts different T cell subsets. We examined the effects of PD-1 blockade on self-reactive CD4+ T cells in mouse models of varying autoimmune susceptibilities. We used insulin-peptide/MHC Class II tetramers to track endogenous insulin-specific CD4+ T cells in diabetes-prone (NOD), and diabetes-resistant (NOR and B6.g7) mice. PD-1 was expressed at lower levels on insulin-specific cells in diabetes-resistant mice compared to cells from NOD mice. Moreover, PD-1 pathway blockade accelerated autoimmunity in all NOD mice and 30% of NOR mice, but B6.g7 mice remained protected from disease. By transferring congenically marked islet-specific CD4+ T cells into pre-diabetic NOD mice, we asked whether anti-PD-L1 reinvigorates anergic cells. Surprisingly, anergic cells remained functionally blunted compared to effector cells after anti-PD-L1, suggesting that established anergic cells were not dependent on PD-1 signaling to maintain their unresponsive state. This work highlights how the differentiation status of a T cell may predetermine its susceptibility to PD-1 blockade, and influence autoimmunity or antitumor responses that ensue.