Abstract
Background Giant cell arteritis (GCA) is a granulomatous vasculitis of medium and large arteries. In GCA-affected arteries, vascular wall is destroyed by tissue-infiltrating CD4 T cells and macrophages, which leads to intramural neoangiogenesis, intimal hyperplasia and luminal occlusion. Objectives This study aimed to examine how CD28 signaling plays a role in vasculitis induction and maintenance and which pathogenic processes are dependent on CD28-mediated T-cell activation. Methods We engrafted human arteries into immunodeficient NSG mice and induced vasculitis by transferring GCA immune cells. Human artery-NSG chimeras were treated with anti-CD28 domain antibody or control Ab. Using tissue transcriptome analysis, immunohistochemistry, flow cytometry and immuno-metabolic analysis, treatment effects were examined in vivo and in vitro. Results Treating such humanized mice with an anti-CD28 domain antibody profoundly reduced tissue-infiltrating T-cells and effectively suppressed vasculitis. Mechanistic studies revealed that CD28 regulated AKT signaling, T-cell proliferation and differentiation of IFN-γ and IL-21-producing effector T-cells. Blocking CD28 signaling disrupted T-cell metabolic fitness; particularly, glucose utilization. Expression of the glucose transporter Glut1 and of glycolytic enzymes as well as mitochondrial oxygen consumption all rely on CD28 signaling. CD28 blockade effectively suppressed vessel wall remodeling processes such as adventitial microvessel formation and intimal hyperplasia as well as induction and maintenance of CD4+CD103+ tissue-resident memory T cells. Conclusion CD28 stimulation provides a metabolic signal required for pathogenic effector functions in GCA, implicating CD28 signaling as a promising therapeutic target.
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call