Published Online
on October 15, 2007

A more recent version of this article appeared on October 30, 2007

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Submitted on April 13, 2007
Accepted on August 27, 2007

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

Nir Grabie PhD, Israel Gotsman MD, Rosa DaCosta BA, Hong Pang MD, George Stavrakis MSc, Manish J. Butte MD, PhD, Mary E. Keir PhD, Gordon J. Freeman MD, PhD, Arlene H. Sharpe MD, PhD, and Andrew H. Lichtman MD, PhD^*

From the Vascular Research Division, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School (N.G., I.G., R.D., H.P., G.S., A.H.L.); Department of Pathology, Harvard Medical School (M.J.B, M.E.K., A.H.S.); and Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School (G.J.F.) Boston, Mass.

^* To whom correspondence should be addressed. E-mail: alichtman{at}rics.bwh.harvard.edu.

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-, and blocking of interferon- 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.

Key words: immune system • inflammation • lymphocytes • myocarditis • endothelium

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