Phenotypic, transcriptomic and functional profiling reveal reduced activation thresholds of CD81 T cells in giant cell arteritis

ABSTRACT

Objectives

Evidence from temporal artery tissue and blood suggests involvement of CD8þ T cells in the pathogenesis of GCA, but their exact role is poorly understood. Therefore, we performed a comprehensive analysis of circulating and lesional CD8þ T cells in GCA patients.

Methods

Circulating CD8þ 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 CD8þ 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 (n¼3 each) was performed for mechanistic insight. Immunohistochemistry was used to detect CD3, CD8, Ki-67, TNF-a and IFN-c in GCA-affected tissues.

Results

GCA patients had decreased numbers of circulating effector memory CD8þ T cells but the percentage of Ki-67-expressing effector memory CD8þ T cells was increased. Circulating CD8þ T cells from GCA patients demonstrated reduced T cell receptor activation thresholds and displayed a gene expression profile that is concurrent with increased proliferation. CD8þ T cells were detected in GCA temporal arteries and aorta. These vascular CD8þ T cells expressed IFN-c but not Ki-67.

Conclusion

In GCA, circulating effector memory CD8þ T cells demonstrate a proliferation-prone phenotype. The presence of CD8þ T cells in inflamed arteries seems to reflect recruitment of circulating cells rather than local expansion. CD8þ T cells in inflamed tissues produce IFN-c, which is an important mediator of local inflammatory responses in GCA.

Authors

van der Geest, Kornelis S.M.; Sandovici, Maria; Nienhues, Peter H.; Slart, Riemer H.J.A.; Heeringa, Peter; Brouwer, Elisabeth; Jiemy, William