Requirement for PD-1 in the induction and maintenance of tolerance differs depending on tolerogenic stimulus (BA8P.118)

Abstract

Abstract The inhibitory receptor Programed Death (PD)-1 interacting with PD-L1 is important for tolerance since blocking this pathway accelerates autoimmunity. However, the mechanisms by which PD-1/PD-L1 contribute to tolerance remain unclear. In this study we tracked endogenous insulin-specific CD4 T cells in mice that are susceptible (NOD) or resistant (B6.g7) to Type 1 Diabetes (T1D). Despite the presence of insulin-reactive CD4 T cells in both strains, anti-PD-L1 precipitated T1D in NOD but not B6.g7 mice. Accelerated T1D in NOD mice correlated with increased numbers of insulin-specific CD4 T cells in the spleen, pancreatic LN, and pancreas. The number of cells increased in the pancreatic LN of B6.g7, but not the spleen or pancreas, suggesting that loss of PD-1 signaling was insufficient to promote trafficking to the pancreas in these mice. Unexpectedly, the breakdown of self tolerance in NOD mice did not rely on PD-1 signals as anergic cells did not change with PD-1 blockade. Rather, PD-1 was more important for regulating effector T cells. This contrasts data using antigen-coupled ECDI-fixed cells to induce anergy in potently activated effector cells during T1D in NOD, where PD-1/PD-L1 ligation is required for both the induction and maintenance of tolerance. This work reveals the role PD-1 signaling has for different contexts of tolerance, and has important therapeutic implications for use of PD-1 inhibitors in patients.