Clinical perspectives for regulatory T cells in transplantation tolerance

Three main types of CD4+ regulatory T cells can be distinguished based upon whether they express Foxp3 and differentiate naturally in the thymus (natural Tregs) or are induced in the periphery (inducible Tregs); or whether they are FoxP3 negative but secrete IL-10 in response to antigen (Tregulatory type 1, Tr1 cells). Adoptive transfer of each cell type has proven highly effective in mouse models at preventing graft vs. host disease (GVHD) and autoimmunity. Although clinical application was initially hampered by low Treg frequency and unfavorable ex vivo expansion properties, several phase I trials are now being conducted to assess their effect on GVHD following hematopoietic stem cell transplantation (HSCT) and in type I diabetes. Human Treg trials for HSCT recipients have preceded other indications because GVHD onset is precisely known, the time period needed for prevention relatively short, initial efficacy is likely to provide life-long protection, and complications of GVHD can be lethal. This review will summarize the clinical trials conducted to date that have employed Tregs to prevent GVHD following HSCT and discuss recent advances in Treg cellular therapy.

► Freshly isolated nTregs have been infused by two groups following HSCT without toxicity. ► Transfer of freshly purified or in vitro expanded Tregs decreases GVHD, although efficacy is limited by nTreg yield. ► Functionally suppressive nTregs can be massively expanded through re-stimulation, allowing ‘off-the-shelf’ Treg banking. ► Future studies are focused on cell surface markers and ways to increase Treg potency, stability, expansion and induction.