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Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice
Israel Gotsman, … , Arlene Sharpe, Andrew H. Lichtman
Israel Gotsman, … , Arlene Sharpe, Andrew H. Lichtman
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2974-2982. https://doi.org/10.1172/JCI31344.
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Research Article Cardiology

Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice

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Abstract

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-α 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.

Authors

Israel Gotsman, Nir Grabie, Rosa Dacosta, Galina Sukhova, Arlene Sharpe, Andrew H. Lichtman

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Figure 1

Effect of PD-L1/PD-L2 deficiency on atherosclerotic burden.

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Effect of PD-L1/PD-L2 deficiency on atherosclerotic burden.
(A and B) Re...
(A and B) Representative cross sections of the ORO-stained aortic sinuses are shown for female LDLR–/– (Control) (A) and PD-L1/2–/–LDLR–/– (PD-L1/2–/–) mice (B) after 10 weeks of high-cholesterol diet (original magnification, ×10). (C and D) Representative longitudinal sections of aortic arch are shown for female LDLR–/– (C) and PD-L1/2–/– mice (D) after 10 weeks of high-cholesterol diet (original magnification, ×100). (E–H) Quantitative analysis of lesions was performed on aortic roots taken after 5 weeks of high-cholesterol diet (E), and on aortic root (F), aortic arch (G), and descending aorta fractional en face lesion area (H), after 10 weeks of high-cholesterol diet. Each data point represents the mean value obtained for each mouse; horizontal bars represent the mean value for each group. †P < 0.01, ‡P < 0.001, ΧP < 0.0001 versus control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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