Role of the PD-1 pathway in regulating islet-reactive CD4 T cells during autoimmune diabetes (123.39)

Abstract

Abstract Engagement of the inhibitory receptor PD-1 with its ligand PD-L1 is critical for preventing Type 1 diabetes in non-obese diabetic (NOD) mice. The mechanism by which PD-1 signaling limits self-reactive CD4 T cells is not well understood. To investigate this we transferred a low number of self-reactive BDC2.5 T cell receptor transgenic CD4+ T cells into prediabetic NOD mice. These cells became activated due to the presence of endogenous antigen. Following activation we administered anti-PD-L1 antibody to block PD-1 signaling and determined the affect on the BDC2.5 cells. PD-1 blockade resulted in an increase in BDC2.5 T cells in the spleen, pancreatic lymph node, and pancreas. This increase correlated with an increase in proliferation in the secondary lymphoid organs measured by CFSE dye dilution. However, it is unclear whether the increase in the pancreas was due to increased proliferation or enhanced recruitment. To investigate the requirement for PD-1 and/or PD-L1 on effector CD4+ T cells, we utilized genetically deficient BDC2.5 T cells. We determined that PD-1 on the BDC2.5 T cell was required to suppress proliferation and recruitment to the pancreas, whereas PD-L1 on the BDC2.5 T cell was dispensable. These data suggest that PD-1 is required on the autoreactive CD4+ T cells and under normal conditions will suppress proliferation in the secondary lymphoid organs and limit recruitment to the pancreas in a cell intrinsic manner.