Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal

The inhibitory protein PD-1 is expressed on activated T cells. Fife and colleagues find that interactions between PD-1 and its ligand PD-1L are needed to maintain tolerance and prevent interactions between tolerized T cells and dendritic cells. Programmed death 1 (PD-1) is an inhibitory molecule expressed on activated T cells; however, the biological context in which PD-1 controls T cell tolerance remains unclear. Using two-photon laser-scanning microscopy, we show here 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. Inhibition of T cell antigen receptor (TCR)-driven stop signals depended on continued interactions between PD-1 and its ligand, PD-L1, as antibody blockade of PD-1 or PD-L1 resulted in lower T cell motility, enhanced T cell–DC contacts and caused autoimmune diabetes. Blockade of the immunomodulatory receptor CTLA-4 did not alter T cell motility or abrogate tolerance. Thus, PD-1–PD-L1 interactions maintain peripheral tolerance by mechanisms fundamentally distinct from those of CTLA-4.