@article {542246,
	title = {Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation.},
	journal = {Arterioscler Thromb Vasc Biol},
	volume = {31},
	number = {5},
	year = {2011},
	month = {2011 May},
	pages = {1100-7},
	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.

CONCLUSIONS: 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.},
	keywords = {Animals, Antibodies, Blocking, Antigens, CD274, Antigens, CD3, Antigens, CD80, Antigens, Surface, Apoptosis, Apoptosis Regulatory Proteins, Atherosclerosis, Bone Marrow Transplantation, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Genes, T-Cell Receptor, Genotype, Hypercholesterolemia, Inflammation, Lipoproteins, LDL, Lymph Nodes, Lymphocyte Activation, Macrophages, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptides, Phenotype, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Receptors, LDL, Signal Transduction, T-Lymphocyte Subsets, T-Lymphocytes, Cytotoxic, Time Factors, Tumor Necrosis Factor-alpha},
	issn = {1524-4636},
	doi = {10.1161/ATVBAHA.111.224709},
	author = {Bu, De-xiu and Tarrio, Margarite and Maganto-Garcia, Elena and Stavrakis, George and Tajima, Goro and Lederer, James and Jarolim, Petr and Freeman, Gordon J and Sharpe, Arlene H and Lichtman, Andrew H}
}
