Impairment of the Programmed Cell Death-1 Pathway Increases Atherosclerotic Lesion Development and Inflammation

Abstract

Objective— Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals on interaction with its 2 ligands, PD-L1 and PD-L2. We studied the contribution of the PD-1 pathway to regulation of T cells that promote atherosclerotic lesion formation and inflammation. Methods and Results— We show that compared with Ldlr −/− control mice, Pd1 −/− Ldlr −/− mice developed larger lesions with more abundant CD4 + and CD8 + T cells and macrophages, accompanied by higher levels of serum tumor necrosis factor-α. Iliac lymph node T cells from Pd1 −/− Ldlr −/− mice proliferated more to αCD3 or oxidized low-density lipoprotein stimulation compared with controls. CD8 + T cells from Pd1 −/− Ldlr −/− mice displayed more cytotoxic activity compared with controls in vivo and in vitro. Administration of a blocking anti-PD-1 antibody increased lesional inflammation in hypercholesterolemic Ldlr −/− mice with more lesional T cells and more activated T cells in paraaortic lymph nodes. The changes in lesional T-cell content when PD-1 was absent or blocked were also observed in bone marrow chimeric Ldlr −/− mice lacking PD-L1 and PD-L2 on hematopoietic cells. Conclusion— PD-1 has an important role in downregulating proatherogenic T-cell responses, and blockade of this molecule for treatment of viral infections or cancer may increase risk of cardiovascular complications.