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_H17 cells under the stimulation of inflamed synovial fibroblasts (SFs). In this study, we made a head-to-head comparison of both T_reg 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.