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

1185 Autoimmunity results from the breakdown of processes designed to maintain self-tolerance. The growing list of costimulatory and inhibitory receptors that influence immune cell activation has been a central concern in immunology for over two decades. CTLA-4 (CD152) is a well established negative regulator of T cell function1. CTLA-4 is rapidly expressed on the surface of T cells after activation and is highly upregulated by engagement of the costimulatory molecule CD28 (ref. 1). CTLA-4 ligation antagonizes early T cell activation by inhibiting interleukin 2 (IL-2) production, cell cycle progression and T cell antigen receptor (TCR) signaling2,3. CTLA-4 and CD28 share the ligands B7-1 (CD80) and B7-2 (CD86)4. Mice deficient in CTLA-4 develop lymphoproliferative disease and die within 3–4 weeks of birth5, which adds further evidence of the critical role of CTLA-4 in controlling T cell responses and immune homeostasis. Programmed death 1 (PD-1 (CD279)) is an inhibitory molecule found on the surface of activated B cells and T cells that has been linked to immune tolerance6. PD-1 is a member of the CD28 and CTLA-4 immunoglobulin superfamily and interacts with two B7 family ligands, PD-L1 (CD274) and PD-L2 (CD273)4. PD-L1 is widely distributed on leukocytes and nonhematopoietic cells in lymphoid and nonlymphoid tissues, including pancreatic islets, whereas PD-L2 is expressed exclusively on dendritic cells (DCs) and monocytes7,8. The PD-1 signaling pathway limits viral clearance during chronic infection by creating an unresponsive state in virus-specific CD8+ T cells called ‘exhaustion’9. In an autoimmune setting, PD-1 is essential for maintaining T cell anergy and preventing autoimmunity10,11. Genetic deletion of PD-1 results in profound and complex multiorgan autoimmune destruction4. Similarly, blocking PD-1–PD-L1 interactions accelerates spontaneous autoimmune diabetes12 and reverses immune tolerance10,11. Together these data support the idea that PD-1 serves a central role as a major inhibitory pathway controlling immunity and suggest that exhaustion and peripheral tolerance are linked mechanistically. Several theories have emerged to explain the mechanism by which PD-1 suppresses T cell activation. PD-L1 may act passively by competing directly with CD28 for B7-1 binding13. In addition, PD-1 may directly recruit phosphatases such as SHP-1 and SHP-2, which interfere with TCR signaling4,14–16. However, the effects of PD-1 engagement during T cell activation are unclear, as in vitro models have not adequately demonstrated the inhibitory activity of PD-1 (ref. 17). In vivo studies of PD-1-mediated inhibition have been limited to global effects on immunity with little evidence that PD-1 engagement directly controls T cell signaling. A well-defined, antigen-specific tolerance model has been used to examine the cellular basis of immunological tolerance with antigenpulsed and fixed antigen-presenting cells (APCs)10. Administration of the islet antigen peptide mimic p31 coupled to chemically fixed APCs reversed diabetes and induced robust, long-term inactivation of islet-specific BDC2.5 TCR–transgenic T cells. Tolerized T cells did not proliferate or produce cytokines in response to TCR stimulation. Although both PD-1 and CTLA-4 interactions were critical for the induction of tolerance, long-term maintenance of the anergic state depended on PD-1–PD-L1 interactions but not on CTLA-4 interactions in the inflamed tissue10. These results indicate that a cellintrinsic mechanism maintains tolerance in the setting of continual exposure to autoantigen.