title: CD11c(+) dendritic cells maintain antigen processing, presentation capabilities, and CD4(+) T-cell priming efficacy under hypercholesterolemic conditions associated with atherosclerosis.
abstract: 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-gamma and tumor necrosis factor-alpha 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.
authors.affiliation: Leducq Center for Cardiovascular Research and Donald W Reynolds Cardiovascular Clinical Research Center, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: René R S
authors.initials: RR
authors.lastname: Packard
authors.forename: Elena
authors.initials: E
authors.lastname: Maganto-García
authors.forename: Israel
authors.initials: I
authors.lastname: Gotsman
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology*; D039521:CD11c Antigen / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000097:blood; D008078:Cholesterol, LDL / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications / Q000209:etiology / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D039521:CD11c Antigen; D002791:Cholesterol, Dietary; D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL; D011948:Receptors, Antigen, T-Cell; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; C032629:acetyl-LDL; D007371:Interferon-gamma; D010047:Ovalbumin