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(Circulation Research. 2008;103:965.)
© 2008 American Heart Association, Inc.

Molecular Medicine

CD11c⁺ Dendritic Cells Maintain Antigen Processing, Presentation Capabilities, and CD4⁺ T-Cell Priming Efficacy Under Hypercholesterolemic Conditions Associated With Atherosclerosis

René R.S. Packard, Elena Maganto-García, Israel Gotsman, Ira Tabas, Peter Libby, Andrew H. Lichtman

From the Leducq Center for Cardiovascular Research and Donald W. Reynolds Cardiovascular Clinical Research Center, Division of Cardiovascular Medicine, Department of Medicine (R.R.S.P., P.L.); and Immunology and Vascular Research Divisions, Department of Pathology (E.M.-G., I.G., A.H.L.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and Departments of Medicine, Anatomy and Cell Biology, and Physiology and Cellular Biophysics (I.T.), Columbia University, New York.

Correspondence to Dr Peter Libby, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave Louis Pasteur, NRB 7, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu

Recent reports suggest dyslipidemia impairs dendritic cell (DC) function and adaptive immunity. This study aimed to characterize the effect of hypercholesterolemia on antigen-presenting cell function of DCs and DC-dependent CD4⁺ T-cell responses. DCs incubated in vitro with acetylated low-density lipoprotein cholesterol with or without an acyl-coenzyme A:cholesterol acyl-transferase inhibitor maintained their ability to prime CD4⁺ T cells. Analysis of T-cell proliferation and interferon- and tumor necrosis factor- production after ex vivo coculture of naïve CD4⁺ T cells with splenic, inguinal, or iliac DCs from low-density lipoprotein receptor–deficient (LDLR^–/–) or apolipoprotein E–deficient (ApoE^–/–) mice fed an atherogenic diet highlighted DC efficacy in effector T-cell generation under hypercholesterolemic conditions. Adoptive transfer of carboxyfluorescein diacetate, succinimidyl ester (CFSE)-labeled naïve CD4⁺ T cells in LDLR^–/– recipients and subsequent immunization demonstrated effective priming of naïve T cells in hypercholesterolemic mice. CFSE dilution analyses revealed that hypercholesterolemic DCs were equipotent in naïve CD4⁺ T-cell priming efficacy with normocholesterolemic DCs. Quantitative real-time PCR and flow cytometric analyses demonstrated that DC expression of multiple molecules involved in antigen processing, presentation, and T-cell stimulation remained unaltered by dyslipidemia. Finally, endogenous antigen-primed CD4⁺ T cells responded equivalently to a secondary ex vivo antigenic challenge, regardless of whether they were primed in vivo under hypercholesterolemic or control conditions, demonstrating that all essential steps in CD4⁺ T-cell responses remain intact under atherogenic conditions. This study affirms that the adaptive immune response prevails under the hypercholesterolemic conditions present in atherosclerosis. In particular, DCs remain functional antigen-presenting cells and maintain their ability to prime CD4⁺ T cells even when cholesterol-loaded.

Key Words: dendritic cells • hypercholesterolemia • atherosclerosis • adaptive immunity