Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with a rising incidence worldwide. The precise etiology 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.
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