Induced, but not natural, regulatory T cells retain phenotype and function following exposure to inflamed synovial fibroblasts

Aberrant number and/or dysfunction of CD4(+) Foxp3(+) Regulatory T cells (T-regs) are associated with the pathogenesis of rheumatoid arthritis (RA). A previous study has demonstrated that thymus-derived, natural T-regs (nT(regs) ) prefer to accumulate in inflamed joints and transdifferentiate to T(H)17 cells under the stimulation of inflamed synovial fibroblasts (SFs). In this study, we made a head-to-head comparison of both T-regs subsets and demonstrated that induced T-regs (iT(regs)), but not nT(regs) retained Foxp3 expression and regulatory function on T effector cells (T-effs) after being primed with inflamed SFs. In addition, iT(regs) inhibited proliferation, inflammatory cytokine production, migration, and invasion ability of collagen-induced arthritis (CIA)-SFs in vitro and in vivo. Moreover, we noted that iT(regs) directly targeted inflamed SFs to treat autoimmune arthritis, while nT(regs) failed to do this. Thus, manipulation of the iT(reg) subset may have a greater potential for prevention or treatment of patients with RA.