Marc Clément1, Yacine Haddad1, Juliette Raffort1, Fabien Lareyre1, Stephen A Newland1, Leanne Master1, James Harrison1, Maria Ozsvar-Kozma1, Patrick Bruneval1, Christoph J Binder1, Soraya Taleb1, Ziad Mallat2. 1. From the Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (M.C., J.R., F.L., S.A.N., L.M., J.H., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, France (Y.H., P.B., S.T., Z.M.); Université Côte d'Azur, CHU, CNRS, Inserm, IRCAN, Nice, France (J.R., F.L.); Department of Vascular Surgery (F.L.) and Clinical Chemistry Laboratory (J.R.), University Hospital of Nice, France; Department of Laboratory Medicine, Medical University of Vienna, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (M.O.-K., C.J.B.); and Universite Paris-Descartes, Hopital Europeen Georges Pompidou, France (P.B.). 2. From the Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (M.C., J.R., F.L., S.A.N., L.M., J.H., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, France (Y.H., P.B., S.T., Z.M.); Université Côte d'Azur, CHU, CNRS, Inserm, IRCAN, Nice, France (J.R., F.L.); Department of Vascular Surgery (F.L.) and Clinical Chemistry Laboratory (J.R.), University Hospital of Nice, France; Department of Laboratory Medicine, Medical University of Vienna, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (M.O.-K., C.J.B.); and Universite Paris-Descartes, Hopital Europeen Georges Pompidou, France (P.B.). zm255@medchl.cam.ac.uk.
Abstract
RATIONALE: Despite an established role for adaptive immune responses in atherosclerosis, the contribution of dendritic cells (DCs) and their various subsets is still poorly understood. OBJECTIVE: Here, we address the role of IRF8 (interferon regulatory factor 8)-dependent DCs (lymphoid CD8α+ and their developmentally related nonlymphoid CD103+ DCs) in the induction of proatherogenic immune responses during high fat feeding. METHODS AND RESULTS: Using a fate-mapping technique to track DCs originating from a DNGR1+ (dendritic cell natural killer lectin group receptor 1) precursor (Clec9a+/creRosa+/EYFP mice), we first show that YFPhiCD11chiMHCIIhi (major histocompatibility complex class II) DCs are present in the atherosclerotic aorta of low-density lipoprotein receptor-deficient (Ldlr-/-) mice and are CD11b-CD103+IRF8hi. Restricted deletion of IRF8 in DCs (Irf8flox/floxCd11cCre ) reduces the accumulation of CD11chiMHCIIhi DCs in the aorta without affecting CD11b+CD103- DCs or macrophages but completely abolishes the accumulation of aortic CD11b-CD103+ DCs. Lymphoid CD8α+ DCs are also deleted. This is associated with a significant reduction of aortic T-cell accumulation and a marked reduction of high-fat diet-induced systemic T-cell priming, activation, and differentiation toward T helper type 1 cells, T follicular helper cells, and regulatory T cells. As a consequence, B-cell activation and germinal center responses to high-fat diet are also markedly reduced. IRF8 deletion in DCs significantly reduces the development of atherosclerosis, predominantly in the aortic sinus, despite a modest increase in total plasma cholesterol levels. CONCLUSIONS: IRF8 expression in DCs plays a nonredundant role in the development of proatherogenic adaptive immunity.
RATIONALE: Despite an established role for adaptive immune responses in atherosclerosis, the contribution of dendritic cells (DCs) and their various subsets is still poorly understood. OBJECTIVE: Here, we address the role of IRF8 (interferon regulatory factor 8)-dependent DCs (lymphoid CD8α+ and their developmentally related nonlymphoid CD103+ DCs) in the induction of proatherogenic immune responses during high fat feeding. METHODS AND RESULTS: Using a fate-mapping technique to track DCs originating from a DNGR1+ (dendritic cell natural killer lectin group receptor 1) precursor (Clec9a+/creRosa+/EYFP mice), we first show that YFPhiCD11chiMHCIIhi (major histocompatibility complex class II) DCs are present in the atherosclerotic aorta of low-density lipoprotein receptor-deficient (Ldlr-/-) mice and are CD11b-CD103+IRF8hi. Restricted deletion of IRF8 in DCs (Irf8flox/floxCd11cCre ) reduces the accumulation of CD11chiMHCIIhi DCs in the aorta without affecting CD11b+CD103- DCs or macrophages but completely abolishes the accumulation of aortic CD11b-CD103+ DCs. Lymphoid CD8α+ DCs are also deleted. This is associated with a significant reduction of aortic T-cell accumulation and a marked reduction of high-fat diet-induced systemic T-cell priming, activation, and differentiation toward T helper type 1 cells, T follicular helper cells, and regulatory T cells. As a consequence, B-cell activation and germinal center responses to high-fat diet are also markedly reduced. IRF8 deletion in DCs significantly reduces the development of atherosclerosis, predominantly in the aortic sinus, despite a modest increase in total plasma cholesterol levels. CONCLUSIONS: IRF8 expression in DCs plays a nonredundant role in the development of proatherogenic adaptive immunity.
Authors: Marc Clement; Juliette Raffort; Fabien Lareyre; Dimitrios Tsiantoulas; Stephen Newland; Yuning Lu; Leanne Masters; James Harrison; Svetlana Saveljeva; Marcella K L Ma; Maria Ozsvar-Kozma; Brian Y H Lam; Giles S H Yeo; Christoph J Binder; Arthur Kaser; Ziad Mallat Journal: Circ Res Date: 2019-10-15 Impact factor: 17.367