Pathogenic Autoimmunity in Atherosclerosis Evolves From Initially Protective Apolipoprotein B <sub>100</sub> –Reactive CD4 <sup>+</sup> T-Regulatory Cells
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- Dennis Wolf
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Teresa Gerhardt
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Holger Winkels
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Nathaly Anto Michel
- Department of Cardiology/Angiology I, University Heart Center Freiburg-Bad Krozingen, Germany (D.W., T.G., N.A.M., X.S., H.H., S.H., L.S.M., P.S., I.H.).
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- Akula Bala Pramod
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Yanal Ghosheh
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Simon Brunel
- Division of Immune Regulation (S.B., D.S., C.A.B.), La Jolla Institute for Immunology, CA.
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- Konrad Buscher
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Jacqueline Miller
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Sara McArdle
- Microscopy Core Facility (S.M.), La Jolla Institute for Immunology, CA.
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- Livia Baas
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Kouji Kobiyama
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Melanie Vassallo
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Erik Ehinger
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Thamotharampillai Dileepan
- Department of Microbiology, University of Minnesota Medical School, Minneapolis (T.D.).
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- Amal Ali
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Maximilian Schell
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Zbigniew Mikulski
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Daniel Sidler
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Takayuki Kimura
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
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- Xia Sheng
- Department of Cardiology/Angiology I, University Heart Center Freiburg-Bad Krozingen, Germany (D.W., T.G., N.A.M., X.S., H.H., S.H., L.S.M., P.S., I.H.).
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- Hauke Horstmann
- Department of Cardiology/Angiology I, University Heart Center Freiburg-Bad Krozingen, Germany (D.W., T.G., N.A.M., X.S., H.H., S.H., L.S.M., P.S., I.H.).
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- Sophie Hansen
- Department of Cardiology/Angiology I, University Heart Center Freiburg-Bad Krozingen, Germany (D.W., T.G., N.A.M., X.S., H.H., S.H., L.S.M., P.S., I.H.).
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- Lucia Sol Mitre
- Department of Cardiology/Angiology I, University Heart Center Freiburg-Bad Krozingen, Germany (D.W., T.G., N.A.M., X.S., H.H., S.H., L.S.M., P.S., I.H.).
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- Peter Stachon
- Department of Cardiology/Angiology I, University Heart Center Freiburg-Bad Krozingen, Germany (D.W., T.G., N.A.M., X.S., H.H., S.H., L.S.M., P.S., I.H.).
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- Ingo Hilgendorf
- Department of Cardiology/Angiology I, University Heart Center Freiburg-Bad Krozingen, Germany (D.W., T.G., N.A.M., X.S., H.H., S.H., L.S.M., P.S., I.H.).
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- Dalia E. Gaddis
- Center for Autoimmunity and Inflammation (D.E.G., C.H., K.L.), La Jolla Institute for Immunology, CA.
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- Catherine Hedrick
- Center for Autoimmunity and Inflammation (D.E.G., C.H., K.L.), La Jolla Institute for Immunology, CA.
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- Chris A. Benedict
- Division of Immune Regulation (S.B., D.S., C.A.B.), La Jolla Institute for Immunology, CA.
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- Bjoern Peters
- Division of Vaccine Discovery (B.P., A.S.), La Jolla Institute for Immunology, CA.
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- Andreas Zirlik
- Department of Cardiology, Medical University Graz, Austria (N.A.M., A.Z.).
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- Alessandro Sette
- Division of Vaccine Discovery (B.P., A.S.), La Jolla Institute for Immunology, CA.
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- Klaus Ley
- Laboratory of Inflammation Biology(D.W., T.G., H.W., A.B.P., Y.G., K.B., J.M., L.B., K.K., M.V., E.E., A.A., M.S., T.K., K.L.), La Jolla Institute for Immunology, CA.
説明
<jats:sec> <jats:title>Background:</jats:title> <jats:p> Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4 <jats:sup>+</jats:sup> T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B <jats:sub>100</jats:sub> (apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (T <jats:sub>H</jats:sub> 1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4 <jats:sup>+</jats:sup> T cells with an atheroprotective, regulatory T cell (T <jats:sub>reg</jats:sub> ) phenotype in healthy individuals. Yet, the function of apoB-reactive T <jats:sub>regs</jats:sub> and their relationship with pathogenic T <jats:sub>H</jats:sub> 1 cells remain unknown. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p> To interrogate the function of autoreactive CD4 <jats:sup>+</jats:sup> T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B <jats:sub>978-993</jats:sub> (apoB <jats:sup>+</jats:sup> ) at the single-cell level. </jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> We found that apoB <jats:sup>+</jats:sup> T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a T <jats:sub>reg</jats:sub> -like transcriptome, although only 21% of all apoB <jats:sup>+</jats:sup> T cells expressed the T <jats:sub>reg</jats:sub> transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB <jats:sup>+</jats:sup> T cells formed several clusters with mixed T <jats:sub>H</jats:sub> signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of T <jats:sub>H</jats:sub> 1, T helper cell type 2 (T <jats:sub>H</jats:sub> 2), and T helper cell type 17 (T <jats:sub>H</jats:sub> 17), and of follicular-helper T cells. ApoB <jats:sup>+</jats:sup> T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic T <jats:sub>H</jats:sub> 1/T <jats:sub>H</jats:sub> 17-like cells with proinflammatory properties and only a residual T <jats:sub>reg</jats:sub> transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed T <jats:sub>H</jats:sub> 1/T <jats:sub>H</jats:sub> 17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB <jats:sup>+</jats:sup> T <jats:sub>regs</jats:sub> in lineage tracing of hyperlipidemic <jats:italic>Apoe</jats:italic> <jats:sup>–/–</jats:sup> mice. In adoptive transfer experiments, converting apoB <jats:sup>+</jats:sup> T <jats:sub>regs</jats:sub> failed to protect from atherosclerosis. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p> Our results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive T <jats:sub>regs</jats:sub> as a novel cellular target in atherosclerosis. </jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 142 (13), 1279-1293, 2020-09-29
Ovid Technologies (Wolters Kluwer Health)