Author + information
- Received October 9, 2018
- Revision received December 6, 2018
- Accepted January 7, 2019
- Published online April 8, 2019.
- Hui Zhang, MD, PhDa,
- Ryu Watanabe, MD, PhDa,
- Gerald J. Berry, MDb,
- Steven G. Nadler, PhDc,
- Jörg J. Goronzy, MD, PhDa and
- Cornelia M. Weyand, MD, PhDa,∗ (, )@StanfordMed
- aDepartment of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California
- bDepartment of Pathology, Stanford University School of Medicine, Stanford, California
- cBristol-Myers Squibb, Princeton, New Jersey
- ↵∗Address for correspondence:
Dr. Cornelia M. Weyand, Department of Medicine, Stanford University School of Medicine, CCSR Building Room 2225, 269 Campus Drive West, Stanford, California 94305-5166.
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-γ 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.
This work was supported by a sponsored research agreement with Bristol-Myers Squibb. This work was supported by the National Institutes of Health grants R01 AR042527, R01 HL117913, R01 AI108906, and P01 HL129941 to Dr. Weyand, and R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191, and I01 BX001669 to Dr. Goronzy. Dr. Zhang has received fellowship support from the Govenar Discovery Fund. Dr. Nadler is employed by and holds shares in Bristol-Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received October 9, 2018.
- Revision received December 6, 2018.
- Accepted January 7, 2019.
- 2019 American College of Cardiology Foundation
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