MHC Class II–Restricted Antigen Presentation by Plasmacytoid Dendritic Cells Drives Proatherogenic T Cell Immunity
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- Andrew P. Sage
- 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...
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- Deirdre Murphy
- 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...
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- Pasquale Maffia
- 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...
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- Leanne M. Masters
- 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...
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- Suleman R. Sabir
- 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...
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- Lauren L. Baker
- 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...
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- Helen Cambrook
- 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...
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- Alison J. Finigan
- 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...
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- Hafid Ait-Oufella
- 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...
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- Gianluca Grassia
- 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...
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- James E. Harrison
- 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...
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- Burkhard Ludewig
- 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...
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- Walter Reith
- 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...
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- Göran K. Hansson
- 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...
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- Boris Reizis
- 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...
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- Stéphanie Hugues
- 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...
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- Ziad Mallat
- 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...
抄録
<jats:sec> <jats:title>Background—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Selective pDC deficiency in vivo was achieved using <jats:italic>CD11c</jats:italic> -Cre × <jats:italic>Tcf4</jats:italic> <jats:sup>–/flox</jats:sup> bone marrow transplanted into <jats:italic>Ldlr</jats:italic> <jats:sup>–/–</jats:sup> mice. Compared with control <jats:italic>Ldlr</jats:italic> <jats:sup>–/–</jats:sup> chimeric mice, <jats:italic>CD11c</jats:italic> -Cre × <jats:italic>Tcf4</jats:italic> <jats:sup>–/flox</jats:sup> mice had reduced atherosclerosis levels. To begin to understand the mechanisms by which pDCs regulate atherosclerosis, we studied chimeric <jats:italic>Ldlr</jats:italic> <jats:sup>–/–</jats:sup> 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 <jats:sup>+</jats:sup> 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 <jats:sup>+</jats:sup> T cell–depleted animals. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>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.</jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 130 (16), 1363-1373, 2014-10-14
Ovid Technologies (Wolters Kluwer Health)