Andrew P Sage1, Deirdre Murphy1, Pasquale Maffia1, Leanne M Masters1, Suleman R Sabir1, Lauren L Baker1, Helen Cambrook1, Alison J Finigan1, Hafid Ait-Oufella1, Gianluca Grassia1, James E Harrison1, Burkhard Ludewig1, Walter Reith1, Göran K Hansson1, Boris Reizis1, Stéphanie Hugues1, Ziad Mallat2. 1. From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (A.P.S., D.M., L.M.M., L.L.B., A.J.F., J.E.H., Z.M.); Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M., S.R.S., H.C., G.G.); Institut National de la Santé et de la Recherche Médicale, Unit 970, Paris Cardiovascular Research Center, Paris, France (H.A., Z.M.); the Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M., G.G.); Institute of Immunobiology, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland (B.L.); the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland (W.R.); Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden (G.K.H.); the Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY (B.R.); and the Department of Pathology, University of Geneva Medical School, CH-1211 Geneva, Switzerland (S.H.). 2. From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (A.P.S., D.M., L.M.M., L.L.B., A.J.F., J.E.H., Z.M.); Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M., S.R.S., H.C., G.G.); Institut National de la Santé et de la Recherche Médicale, Unit 970, Paris Cardiovascular Research Center, Paris, France (H.A., Z.M.); the Department of Pharmacy, University of Naples Federico II, Naples, Italy (P.M., G.G.); Institute of Immunobiology, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland (B.L.); the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland (W.R.); Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden (G.K.H.); the Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY (B.R.); and the Department of Pathology, University of Geneva Medical School, CH-1211 Geneva, Switzerland (S.H.). zm255@medchl.cam.ac.uk.
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.
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.
Authors: Louise J Young; Nicholas S Wilson; Petra Schnorrer; Anna Proietto; Toine ten Broeke; Yohei Matsuki; Adele M Mount; Gabrielle T Belz; Meredith O'Keeffe; Mari Ohmura-Hoshino; Satoshi Ishido; Willem Stoorvogel; William R Heath; Ken Shortman; Jose A Villadangos Journal: Nat Immunol Date: 2008-10-12 Impact factor: 25.606
Authors: Andreas Hermansson; Daniel K Johansson; Daniel F J Ketelhuth; John Andersson; Xinghua Zhou; Göran K Hansson Journal: Circulation Date: 2011-02-28 Impact factor: 29.690
Authors: Jesse W Williams; Andrew Elvington; Skyler Kessler; Mary Wohltmann; Gregory F Wu; Gwendalyn J Randolph Journal: Immunohorizons Date: 2019-01-21