Circulating Treg cells from patients with cerebral aneurysms displayed deficiency in ICOS expression and function.

Inducible costimulator (ICOS) is a member of the CD28 family. When activated, ICOS signalling promotes FOXP3 CNS2 gene demethylation and stabilizes Treg differentiation. Cerebral aneurysm (CA) is the local ballooning of the cerebral vasculature, characterized by higher levels of inflammation mediators and tissue remodelling. FOXP3+ Treg cell dysfunction may contribute to CA pathogenesis. In this study, the expression and function of ICOS in Treg cells was investigated. Circulating CD4+ CD25hi T cells from CA subjects demonstrated significantly lower levels of ICOS expression than circulating CD4+ CD25hi T cells from healthy subjects. In both healthy subjects and CA subjects, FOXP3+ Treg cells were highly concentrated in the ICOS+ fraction of CD4+ CD25hi T cells. Anti-ICOS costimulation, in combination with anti-CD3 and IL-2, significantly increased FOXP3 expression in CD4+ CD25hi ICOS+ T cells but not in CD4+ CD25hi ICOS- T cells. In addition, anti-CD3/IL-2 and anti-ICOS costimulation significantly elevated the expression of IL-10 and TGF-β, decreased the expression of IL-17, and enhanced CD4+ CD25hi ICOS+ T cell-mediated suppression of autologous CD4+ CD25- Tconv proliferation. Interestingly, CD4+ CD25hi ICOS+ T cells from CA subjects presented lower responsiveness toward anti-ICOS costimulation than CD4+ CD25hi ICOS+ T cells from healthy subjects. Overall, these results demonstrated that ICOS signalling could significantly improve FOXP3 expression and enhance Treg functional potency. However, circulating Treg cells from CA patients displayed reduced ICOS expression and lower responsiveness toward anti-ICOS stimulation.