Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis

Abstract

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 CD226highCD8+ 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 CD226highCD8+ 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.

IL-13 mediates collagen deposition via STAT6 and microRNA-135b: a role for epigenetics

“…They also found this CD8+ T cell production of IL-13 is associated with diffuse cutaneous SSc more so than limited SSc 25 . This has also been verified in a recent study with isolated CD8+ T cells 26 . It has also been shown that CD8+ T cells isolated from patients with SSc mediates increased collagen1A and fibronectin expression in dermal fibroblasts in culture and that this can be blocked by incubation with an anti-IL-13 antibody, but not by an anti-IL-4 antibody or isotype control indicating this is IL-13 specific and not mediated through IL-4.…”

The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4 + T cells

“…The involvement of CD226 in the production of cytokines by immune cells has been mostly studied in NK and CD8 + T cells. CD226 + CD8 + T cells have been shown to produce more IL-4, IL-5, IL-13, and IFN- than their CD226-negative counterparts (40). In NK cells, CD226 triggers production of IFN-, IL-6, and GM-CSF (38,41).…”

Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis

“…In SSc, Th2 cells, Th17 cells, Th1 cells, Th22 cells, Treg cells, T follicular helper (Tfh) cells, and CD8 + T cells have all been implicated in the pathogenic process (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). However, no previous studies have used quantitative approaches to enumerate T cell subsets within SSc lesions.…”