ICOS⁺ follicular regulatory T cells are implicated in the pathogenesis of ulcerative colitis

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with a rising incidence worldwide. The precise aetiology is unclear, but aberrant regulatory T cell (Treg) responses have been documented in active UC patients. Follicular regulatory T cell (Tfr) is a recently identified subset of Treg cells. In this study, the role of ICOS in Tfr cells, which is a costimulatory molecule shown to stabilize and promote Treg differentiation, was investigated in UC patients. We found that with increasing UC severity, the frequency of ICOS⁺ CD4 T cells was increased, but the level of ICOS expression by ICOS⁺ CD4 T cells was decreased. ICOS⁺ cells were highly enriched in follicular regulatory T cells (Tfr), which is a subset of Treg cells characterized by CD25⁺ CD127^- CXCR5⁺ Foxp3⁺ phenotype. Anti-CD3, anti-CD3/CD28, or anti-CD3/ICOS had all significantly increased the expression of Foxp3 and IL-10, and among the three stimulation methods, anti-CD3/ICOS was most effective at enhancing Foxp3 and IL-10 expression. Moreover, anti-CD3/ICOS-stimulated Tfr cells could suppress conventional T cell proliferation in an IL-10-dependent manner. Interestingly, anti-CD3/ICOS stimulation was less effective in UC-Mild and UC-Active patients compared to that in healthy and UC-Remission patients. In addition, UC patients presented impairment in ICOS upregulation following anti-CD3 stimulation. Overall, these data indicated that ICOS⁺ Tfr cells were dysregulated in UC patients and the level of dysregulation was associated with the severity of UC, suggesting that ICOS⁺ Tfr cells could serve as a biomarker of the progression of UC.