Induced Regulatory T Cells as Immunotherapy in Allotransplantation and Autoimmunity: Challenges and Opportunities.

Regulatory T cells (Tregs) play a crucial role in the homeostasis of the immune response. Tregs are mainly generated in the thymus and are characterized by the expression of Foxp3, which is considered the Treg master transcription factor. In addition, Tregs can be induced from naïve CD4+ T cells to express Foxp3 under specific conditions both in vivo (pTregs) and in vitro (iTregs). Both subsets tTregs and pTregs are necessary for the establishment of immune tolerance to self and non-self antigens. Although it has been postulated that iTregs may be less stable compared to tTregs, mainly due to epigenetic differences, accumulating evidence in animal models shows that iTregs are stable in vivo and could be used for the treatment of inflammatory disorders including autoimmune diseases and allogeneic transplant rejection. In this review, we describe the biological characteristics of induced T regs, the key factors involved in iTreg transcriptional, metabolic and epigenetic regulation and discuss recent advances for de novo generation of stable Tregs and their use as immunotherapeutic tools in different experimental models. Moreover, we discuss the challenges and considerations for the application of iTregs in clinical trials and describe the new approaches proposed to achieve in vivo stability, including functional or metabolic reprogramming and epigenetic editing.