Figure1. Development of natural and induced regulatory T cells.

Thymus-derived “natural” regulatory T cells (nTreg) are actively selected upon high avidity TCR/self peptide-loaded MHC interactions, express the forkhead-winged helix transcription factor family member, Foxp3, and are fundamental in the process of self-tolerance, so-called “dominant tolerance”. Conventionally selected naïve Foxp3⁻ CD4⁺ T cells can be “converted” into induced Foxp3⁺Treg (iTreg) in response to self or non-self antigens encountered post thymically in the periphery. TGF-β is required for both early nTreg development in the thymus and for peripheral induction of iTreg. TGF-β is also able to promote, in the presence of inflammatory cytokines such as IL-6, the development of pro-inflammatory T_H17 cells. The vitamin A metabolite, retinoic acid (RA), is capable of inhibit the TGF-β/IL-6–driven induction of pro-inflammatory T_H17 cells and simultaneously promote the TGF-β-dependent peripheral differentiation of anti-inflammatory Foxp3⁺ iTregs.