MHC class II-restricted antigen presentation by plasmacytoid dendritic cells drives proatherogenic T cell immunity

Sage, A. P. et al. (2014) MHC class II-restricted antigen presentation by plasmacytoid dendritic cells drives proatherogenic T cell immunity. Circulation, 130(16), pp. 1363-1373. (doi:10.1161/CIRCULATIONAHA.114.011090) (PMID:25223984) (PMCID:PMC4428652)

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Abstract

Background—Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and are important regulators of immuno-inflammatory diseases. However, their role in atherosclerosis remains elusive. Methods and Results—Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Selective pDC deficiency in vivo was achieved using CD11c-Cre × Tcf4–/flox bone marrow transplanted into Ldlr–/– mice. Compared with control Ldlr–/– chimeric mice, CD11c-Cre × Tcf4–/flox mice had reduced atherosclerosis levels. To begin to understand the mechanisms by which pDCs regulate atherosclerosis, we studied chimeric Ldlr–/– mice with selective MHCII deficiency on pDCs. Significantly, these mice also developed reduced atherosclerosis compared with controls without reductions in pDC numbers or changes in conventional DCs. MHCII-deficient pDCs showed defective stimulation of apolipoprotein B100–specific CD4+ T cells in response to native low-density lipoprotein, whereas production of interferon-α was not affected. Finally, the atheroprotective effect of selective MHCII deficiency in pDCs was associated with significant reductions of proatherogenic T cell–derived interferon-γ and lesional T cell infiltration, and was abrogated in CD4+ T cell–depleted animals. Conclusions—This study supports a proatherogenic role for pDCs in murine atherosclerosis and identifies a critical role for MHCII-restricted antigen presentation by pDCs in driving proatherogenic T cell immunity.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sabir, Dr Suleman and Maffia, Dr Pasquale and Grassia, Dr Gianluca and Cambrook, Dr Helen
Authors: Sage, A. P., Murphy, D., Maffia, P., Masters, L. M., Sabir, S., Baker, L. L., Cambrook, H., Finigan, A. J., Ait-Oufella, H., Grassia, G., Harrison, J. E., Ludewig, B., Reith, W., Hansson, G. K., Reizis, B., Hugues, S., and Mallat, Z.
Subjects:Q Science > QR Microbiology > QR180 Immunology
R Medicine > RM Therapeutics. Pharmacology
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Circulation
Publisher:American Heart Association
ISSN:0009-7322
ISSN (Online):1524-4539
Copyright Holders:Copyright © 2014 American Heart Association
First Published:First published in Circulation 130(16):1363-1373
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
614711Defining innate and adaptive immune functions of plasmacytoid dendritic cells in atherosclerosis.Pasquale MaffiaBritish Heart Foundation (BHF)PG/12/81/29897III -IMMUNOLOGY