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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antibodies, Blocking / pharmacology
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Antigens, Surface / genetics
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Antigens, Surface / metabolism*
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Apoptosis
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / deficiency
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Atherosclerosis / genetics
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Atherosclerosis / immunology
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Atherosclerosis / metabolism*
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Atherosclerosis / pathology
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B7-1 Antigen / genetics
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B7-1 Antigen / metabolism
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B7-H1 Antigen
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Bone Marrow Transplantation
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CD3 Complex / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cell Proliferation
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Cells, Cultured
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Disease Models, Animal
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Genes, T-Cell Receptor
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Genotype
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Hypercholesterolemia / genetics
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Hypercholesterolemia / immunology
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Hypercholesterolemia / metabolism
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism*
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Inflammation / pathology
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Lipoproteins, LDL / metabolism
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Lymphocyte Activation* / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Male
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Peptides / deficiency
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Peptides / genetics
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Phenotype
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Programmed Cell Death 1 Ligand 2 Protein
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Programmed Cell Death 1 Receptor
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Receptors, LDL / deficiency
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Receptors, LDL / genetics
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Signal Transduction
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism*
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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Time Factors
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Tumor Necrosis Factor-alpha / blood
Substances
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Antibodies, Blocking
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Antigens, Surface
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Apoptosis Regulatory Proteins
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B7-1 Antigen
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B7-H1 Antigen
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CD3 Complex
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Cd274 protein, mouse
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Lipoproteins, LDL
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Membrane Glycoproteins
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Pdcd1 protein, mouse
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Pdcd1lg2 protein, mouse
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Peptides
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Programmed Cell Death 1 Ligand 2 Protein
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Programmed Cell Death 1 Receptor
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Receptors, LDL
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Tumor Necrosis Factor-alpha
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oxidized low density lipoprotein