Increased CD226 expression on CD8⁺ T cells is associated with upregulated cytokine production and endothelial cell injury in patients with systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8⁺ T cells can be detected in peripheral blood and lungs of SSc patients, effector memory CD8⁺ T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8⁺ T cells remain incompletely understood. In this study, we performed DNA microarray analysis of the sort-purified effector memory CD8⁺ T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1 [DNAM-1]), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226^highCD8⁺ T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Furthermore, CD226⁺CD8⁺T cells produced higher amount of various cytokines than CD226- ones, and CD226^highCD8⁺ T cells from SSc patients showed upregulated IL-13 production and positive correlation with the cytotoxic capacity of CD8⁺ T cells against HUVECs. Finally, the neutralization of CD226 in CD8⁺ T cells impaired costimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8⁺ T cells reflects disease severity and is involved in SSc pathogenesis via the production of various cytokines, including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.