Impairment of the Programmed Cell Death-1 Pathway Increases Atherosclerotic Lesion Development and Inflammation
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.
- Received December 2, 2010.
- Accepted February 25, 2011.
- © 2011 American Heart Association, Inc.