ABSTRACT CD25 + FOXP3 + regulatory T (Treg) cells are naturally present in the immune system and play a critical role in maintaining immunological self‐tolerance. Naturally occurring Treg (nTreg) cells have been clinically investigated for the treatment of autoimmune diseases and for the induction of transplantation tolerance. Although recent clinical trials of nTreg‐based cell therapy have demonstrated promising results, several issues remain to be addressed to achieve more effective and stable Treg‐mediated immune suppression and tolerance induction. Another strategy for antigen‐specific Treg cell therapy involves the artificial conversion of antigen‐specific conventional T cells into in vitro–induced Treg (iTreg) cells. However, conventional iTregs have faced several challenges related to their induction efficiency, stability, and functionality, including the failure to establish a Treg‐specific epigenetic profile, such as DNA demethylation. Nevertheless, several studies have improved both the quality and the conversion efficiency of iTregs. In particular, the CDK8/19 inhibitor AS2863619 has been identified as a potent FOXP3 inducer in effector/memory T cells. In addition, ascorbate treatment or deprivation of CD28 co‐stimulatory signaling induces a Treg‐type epigenome in iTregs. These advances have enabled the generation of stable and functional iTregs (S/F‐iTregs). This review provides an overview of the research and development of nTregs and iTregs, including recent findings on S/F‐iTreg cell products and their potential clinical applications.
Norihisa Mikami (Wed,) studied this question.