Endothelial Programmed Death-1 Ligand 1 (PD-L1) Regulates CD8 ⁺ T-Cell–Mediated Injury in the Heart

Abstract

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-γ, and blocking of interferon-γ 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.

Functional Tolerance of CD8+ T Cells Induced by Muscle-Specific Antigen Expression

“…In this regard, it is interesting to note that PD-1-deficient mice develop spontaneously a lethal dilated cardiomyopathy on BALB/c background (52), due to autoantibodies directed against the cardiac muscle autoantigen, troponin I (53). Moreover, PD-1 ligand 1 (PD-L1), one of the two known ligands of PD-1, was recently shown to regulate CD8 ϩ T cell mediated injury in a mouse model of CD8 ϩ T cell-mediated myocarditis (54). In humans, PD-L1 was also shown to be expressed in muscle biopsy specimens of patients with polymyositis, dermatomyositis, or inclusion body myositis, especially in areas of strong inflammation (55).…”

Autoimmune Mechanisms Underlying Dilated Cardiomyopathy

“…In addition to antigenpresenting cells, programmed death (PD)-1 receptors are present in cardiac endothelial cells, among which PD-L1 suppresses the cell-mediated immune response in acute myocarditis. 7 Abnormalities of cell-mediated immunity are also observed in DCM. It has been reported that suppressor T cells are decreased and helper T cells are increased in DCM patients, whereas increased MHC class II expression has been noted in studies of myocardial biopsy specimens.…”

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

“…13 The known ligands for PD-1 are the B7 family molecules PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), [14][15][16][17][18][19][20] which are cell membrane-bound glycoproteins that share 40% amino acid homology to each other. In normal human tissues, PD-L1 is expressed by myeloid dendritic cells (DC), macrophages, placental trophoblasts, myocardial endothelium and cortical thymic epithelial cells, 21,22 whereas PD-L2 is expressed by DC, macrophages, placental endothelium and medullary thymic epithelial cells. 23,24 Binding of PD-1 to either ligand can inhibit T-cell proliferation and cytokine secretion.…”