Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice.
T lymphocyte responses promote proatherogenic inflammatory events, which are influenced by costimulatory molecules of the B7 family. Effects of negative regulatory members of the B7 family on atherosclerosis have not been described. Programmed death-ligand 1 (PD-L1) and PD-L2 are B7 family members expressed on several cell types, which inhibit T cell activation via binding to programmed death-1 (PD-1) on T cells. In order to test whether the PD-1/PD-L pathway regulates proatherogenic T cell responses, we compared atherosclerotic lesion burden and phenotype in hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice and LDLR(-/-) controls. PD-L1/2 deficiency led to significantly increased atherosclerotic burden throughout the aorta and increased numbers of lesional CD4(+) and CD8(+) T cells. Compared with controls, PD-L1/2(-/-)LDLR(-/-) mice had iliac lymphadenopathy and increased numbers of activated CD4(+) T cells. Serum levels of TNF-alpha were higher in PD-L1/2(-/-)LDLR(-/-) mice than in controls. PD-L1/2-deficient APCs were more effective than control APCs in activating CD4(+) T cells in vitro, with or without cholesterol loading. Freshly isolated APCs from hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice stimulated greater T cell responses than did APCs from hypercholesterolemic controls. Our findings indicate that the PD-1/PD-L pathway has an important role in downregulating proatherogenic T cell response and atherosclerosis by limiting APC-dependent T cell activation.
Gotsman
Israel
I
Vascular Research Division, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Grabie
Nir
N
Dacosta
Rosa
R
Sukhova
Galina
G
Sharpe
Arlene
A
Lichtman
Andrew H
AH
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000954:Antigens, Surface / Q000235:genetics / Q000502:physiology*; D001011:Aorta / Q000473:pathology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D060890:B7-H1 Antigen; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000097:blood; D006937:Hypercholesterolemia / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D002784:Cholesterol