1. MHC Class II-restricted antigen presentation by plasmacytoid dendritic cells drives proatherogenic T cell immunity.
- Author
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Sage AP, Murphy D, Maffia P, Masters LM, Sabir SR, Baker LL, Cambrook H, Finigan AJ, Ait-Oufella H, Grassia G, Harrison JE, Ludewig B, Reith W, Hansson GK, Reizis B, Hugues S, and Mallat Z
- Subjects
- Adaptive Immunity immunology, Animals, Aorta cytology, 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, Cell Communication immunology, Cells, Cultured, Dendritic Cells cytology, Flow Cytometry, Mice, Inbred C57BL, Mice, Knockout, Receptors, LDL genetics, Receptors, LDL immunology, Transcription Factor 4, Antigen-Presenting Cells immunology, Atherosclerosis immunology, Atherosclerosis pathology, CD4-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Histocompatibility Antigens Class II immunology
- 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., (© 2014 American Heart Association, Inc.)
- Published
- 2014
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