Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation

PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cell s, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of periphe ral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-LI) is a member of the B7 gene family. Engageme nt of PD-1 by PD-L1 leads to the inhibition of T cell rcceptor-mediated lym phocyte proliferation and cytokine secretion. In addition, PD-1 signaling c an inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues su ch as heart and lung. The relative levels of inhibitory PD-L1 and costimula tory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential int eraction with PD-1 may subsequently determine the extent of immune response s at sites of inflammation.