CD28 Signaling Controls Metabolic Fitness of Pathogenic T Cells in Medium and Large Vessel Vasculitis

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:73

Article

Zhang, Hui¹  Watanabe, Ryu¹  Berry, Gerald J.²  Nadler, Steven G.³  Goronzy, Jorg J.¹  Weyand, Cornelia M.¹ 

[1] Stanford Univ, Sch Med, Dept Med, Div Immunol & Rheumatol, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[3] Bristol Myers Squibb, Princeton, NJ USA

关键词: CD28;    giant cell arteritis;    glycolysis;    immunometabolism;    T cell;    vasculitis;   

DOI  :  10.1016/j.jacc.2019.01.049

来源: Elsevier

【 摘 要 】

BACKGROUND In giant cell arteritis, vessel-wall infiltrating CD4 T cells and macrophages form tissue-destructive granulomatous infiltrates, and the artery responds with a maladaptive response to injury, leading to intramural neoangiogenesis, intimal hyperplasia, and luminal occlusion. Lesion-residing T cells receive local signals, which represent potential therapeutic targets. OBJECTIVES The authors examined how CD28 signaling affects vasculitis induction and maintenance, and which pathogenic processes rely on CD28-mediated T-cell activation. METHODS Vasculitis was induced by transferring peripheral blood mononuclear cells from giant cell arteritis patients into immunodeficient NSG mice engrafted with human arteries. Human artery-NSG chimeras were treated with anti-CD28 domain antibody or control antibody. Treatment effects and immunosuppressive mechanisms were examined in vivo and in vitro applying tissue transcriptome analysis, immunohistochemistry, flow cytometry, and immunometabolic analysis. RESULTS Blocking CD28-dependent signaling markedly reduced tissue-infiltrating T cells and effectively suppressed vasculitis. Mechanistic studies implicated CD28 in activating AKT signaling, T-cell proliferation and differentiation of IFN-gamma and IL-21-producing effector T cells. Blocking CD28 was immunosuppressive by disrupting T-cell metabolic fitness; specifically, the ability to utilize glucose. Expression of the glucose transporter Glut1 and of glycolytic enzymes as well as mitochondrial oxygen consumption were all highly sensitive to CD28 blockade. Also, induction and maintenance of CD4(+)CD103(+) tissue-resident memory T cells, needed to replenish the vasculitic infiltrates, depended on CD28 signaling. CD28 blockade effectively suppressed vasculitis-associated remodeling of the vessel wall. CONCLUSIONS CD28 stimulation provides a metabolic signal required for pathogenic effector functions in medium and large vessel vasculitis. Disease-associated glycolytic activity in wall-residing T-cell populations can be therapeutically targeted by blocking CD28 signaling. (C) 2019 by the American College of Cardiology Foundation.

【 授权许可】

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