Programmed death-1 promotes tolerance by blocking the T cell receptor-induced stop signal. (167.26)

Abstract

Abstract Programmed death-1 (PD-1) and CTLA-4 are inhibitory receptors expressed on activated T cells that are critical for preventing autoimmunity. However, the biological context in which PD-1 and CTLA-4 control T cell tolerance is not fully understood. In this study we used an antigen specific diabetes model and T cell dynamic motility during the induction and maintenance of tolerance in vivo by two-photon imaging. Using this system we demonstrate that unlike naive or activated islet antigen-specific T cells, tolerized islet antigen-specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. However, blocking interactions between PD-1 and PD-L1 altered the dynamic T cell motility and caused the breakdown in peripheral tolerance resulting in autoimmune diabetes. Neutralizing CTLA-4, on the other hand, did not impact tolerized T cell motility in vivo or clinical disease. The ability of PD-1 to influence the T-cell stop signal was antigen dependent, since T cell motility and T cell-DC contact times were unaffected by PD-L1 neutralization in non-draining (inguinal) LNs. These data provide in vivo evidence that PD-1 -PD-L1 interactions are critical for the maintenance of peripheral tolerance and prevention of autoimmunity. Further, the effects of PD-1 are fundamentally distinct from those of CTLA-4 and suggest unique mechanisms of action for these two inhibitory receptors.