Phenotypic, transcriptomic and functional profiling reveal reduced activation thresholds of CD8(+) T cells in giant cell arteritis

Objectives Evidence from temporal artery tissue and blood suggests involvement of CD8(+) T cells in the pathogenesis of GCA, but their exact role is poorly understood. Therefore, we performed a comprehensive analysis of circulating and lesional CD8(+) T cells in GCA patients. Methods Circulating CD8(+) T cells were analysed for differentiation status (CD45RO, CCR7), markers of activation (CD69 and CD25) and proliferation (Ki-67) in 14 newly diagnosed GCA patients and 18 healthy controls by flow cytometry. Proliferative capacity of CD8(+) T cells upon anti-CD3 and anti-CD3/28 in vitro stimulation was assessed. Single-cell RNA sequencing of peripheral blood mononuclear cells of patients and controls (n = 3 each) was performed for mechanistic insight. Immunohistochemistry was used to detect CD3, CD8, Ki-67, TNF-alpha and IFN-gamma in GCA-affected tissues. Results GCA patients had decreased numbers of circulating effector memory CD8(+) T cells but the percentage of Ki-67-expressing effector memory CD8(+) T cells was increased. Circulating CD8(+) T cells from GCA patients demonstrated reduced T cell receptor activation thresholds and displayed a gene expression profile that is concurrent with increased proliferation. CD8(+) T cells were detected in GCA temporal arteries and aorta. These vascular CD8(+) T cells expressed IFN-gamma but not Ki-67. Conclusion In GCA, circulating effector memory CD8(+) T cells demonstrate a proliferation-prone phenotype. The presence of CD8(+) T cells in inflamed arteries seems to reflect recruitment of circulating cells rather than local expansion. CD8(+) T cells in inflamed tissues produce IFN-gamma, which is an important mediator of local inflammatory responses in GCA.