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Abstract Number: 2918

Metabolic Signatures of Pathogenic T Cells in Medium and Large Vessel Vasculitis

Mitsuhiro Akiyama 1, Hui Zhang 1, Ryu Watanabe 1, Toshihisa Maeda 2, Gerald Berry 1, Jorg Goronzy 1 and Cornelia Weyand1, 1Stanford University, Stanford, CA, 2Matsubara Mayflower Hospital, Kobe, Japan

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: giant cell arteritis, large vessel vasculitis and metabolism, T cells, Vasculitis

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Session Information

Date: Wednesday, November 13, 2019

Session Title: 6W024: Vasculitis – Non-ANCA-Associated & Related Disorders III: Large Vessel Vasculitis Pathogenesis & Imaging (2918–2923)

Session Type: ACR Abstract Session

Session Time: 11:00AM-12:30PM

Background/Purpose: Giant cell arteritis (GCA) is an autoimmune vasculitis that causes aortic arch syndrome, blindnesss, and stroke. Embedded in granulomatous infiltrates, CD4 T cells persist over long periods in the inflamed vessel wall where they drive wall remodeling, intramural neoangiogenesis, intimal hyperplasia and luminal occulsion. To survive and function in a nonlymphoid tissue environment, T cells need access to nutrient supply and communicate with their surroundings through metabolic signals. Signaling pathways regulating the metabolic profile of tissue-residing T cells are currently unknown.

Methods: Metabolic gene expression was assessed in tissue biopsies from patients with temporal arteritis and in circulating CD4 T cells from patients with active GCA. Antibody blocking studies were performed in human artery-SCID chimeric mice. Effector cell differentiation was analyzed by detecting intracellular cytokines by flow cytometry. Intramural microvesssels and intimal thickness were quantified by immunohistochemistry.

Results: When compared to age-matched controls, CD4 T cells from GCA patients were characterized by high expression of the glucose transporter GLUT1 and induction of the glycolytic machinery (P < 0.001). Transcription factors relevant for glucose utilization, such as c-myc and HIF-1a, were strongly upregulated (P < 0.001). Tissue-residency of CD4 T cells was linked to GLUT1hi expression (P < 0.001). Upregulation of the metabolic machinery was dependent on CD28 signalinng via activation of the AKT signaling pathway. Costimulation through CD28 induced GLUT1 expression (P < 0.01), glycolytic enzymes (P < 0.05) and mitochondrial oxygen consumption (P < 0.05). Multiple disease-relevant processes required engagement of CD28 and enhanced glycolytic flux, including effector T cells differentiation into IFN-gamma producing Th1 cells and IL-21-producing Tfh cells, intramural neoangiogenesis and hyperplasia of the intimal layer. Notably, CD28 costimulation was needed to sustain CD4+CD103+ tissue-resident memory T cells that secure long-term persistence of vasculitic infiltrates.

Conclusion: CD4 T cells in GCA patients are metabolically reprogrammed, relying on massive upregulation of glucose uptake and breakdown. In the tissue microenvironment, unopposed CD28 costimulation enables optimal utilization of glucose. Pathogenic remodeling of the vessel wall is metabolically controlled, identifying new therapeutic opportunities through metabolic interference.


Disclosure: M. Akiyama, None; H. Zhang, None; R. Watanabe, None; T. Maeda, None; G. Berry, None; J. Goronzy, None; C. Weyand, Kiniska Pharmaceuticals, 2.

To cite this abstract in AMA style:

Akiyama M, Zhang H, Watanabe R, Maeda T, Berry G, Goronzy J, Weyand C. Metabolic Signatures of Pathogenic T Cells in Medium and Large Vessel Vasculitis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/metabolic-signatures-of-pathogenic-t-cells-in-medium-and-large-vessel-vasculitis/. Accessed January 30, 2023.
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