Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell-mediated injury in the heart

Background - PD-L1 and PD-L2 are ligands for the inhibitory receptor programmed death-1 (PD-1), which is an important regulator of immune responses. PD-L1 is induced on cardiac endothelial cells under inflammatory conditions, but little is known about its role in regulating immune injury in the heart. Methods and Results - Cytotoxic T-lymphocyte - mediated myocarditis was induced in mice, and the influence of PD-L1 signaling was studied with PD-L1/L2 - deficient mice and blocking antibodies. During cytotoxic T-lymphocyte-induced myocarditis, the upregulation of PD-L1 on cardiac endothelia was dependent on T-cell- derived interferon-gamma, and blocking of interferon-gamma signaling worsened disease. Genetic deletion of both PD-1 ligands [PD-L1/2((-/-))], as well as treatment with PD-L1 blocking antibody, transformed transient myocarditis to lethal disease, in association with widespread polymorphonuclear leukocyte-rich microabscesses but without change in cytotoxic T-lymphocyte recruitment. PD-L1/2((-/-)) mice reconstituted with bone marrow from wild- type mice remained susceptible to severe disease, which demonstrates that PD-L1 on non-bone marrow-derived cells confers the protective effect. Finally, depletion of polymorphonuclear leukocytes reversed the enhanced susceptibility to lethal myocarditis attributable to PD-L1 deficiency. Conclusions - Myocardial PD-L1, mainly localized on endothelium, is critical for control of immune- mediated cardiac injury and polymorphonuclear leukocyte inflammation.