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.

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.

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.