MHC Class II–Restricted Antigen Presentation by Plasmacytoid Dendritic Cells Drives Proatherogenic T Cell Immunity

• Published in: Circulation (New York, N.Y.) Vol. 130; no. 16; pp. 1363 - 1373
• Main Authors: Sage, Andrew P, Murphy, Deirdre, Maffia, Pasquale, Masters, Leanne M, Sabir, Suleman R, Baker, Lauren L, Cambrook, Helen, Finigan, Alison J, Ait-Oufella, Hafid, Grassia, Gianluca, Harrison, James E, Ludewig, Burkhard, Reith, Walter, Hansson, Göran K, Reizis, Boris, Hugues, Stéphanie, Mallat, Ziad
• Format: Journal Article
• Language: English
• Published: United States by the American College of Cardiology Foundation and the American Heart Association, Inc 14.10.2014
• Subjects: Adaptive Immunity - immunology; Animals; Antigen-Presenting Cells - immunology; Aorta - cytology; Atherosclerosis - immunology; Atherosclerosis - pathology; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - immunology; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; Cell Communication - immunology; Cells, Cultured; Dendritic Cells - cytology; Dendritic Cells - immunology; Flow Cytometry; Histocompatibility Antigens Class II - immunology; Medicin och hälsovetenskap; Mice, Inbred C57BL; Mice, Knockout; Receptors, LDL - genetics; Receptors, LDL - immunology; Transcription Factor 4; atherosclerosis; dendritic cells; lymphocytes; immunity; antigen presentation
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.114.011090

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 bone marrow transplanted into Ldlr mice. Compared with control Ldlr chimeric mice, CD11c-Cre × Tcf4 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.