Translational Mini-Review Series on Th17 Cells: Induction of interleukin-17 production by regulatory T cells

P>Uncommitted (naive) CD4+ T helper cells (Thp) can be induced to differentiate to specific lineages according to the local cytokine milieu, towards T helper type 1 (Th1), Th2, Th17 and regulatory T cell (T-reg) phenotypes in a mutually exclusive manner. Each phenotype is characterized by unique signalling pathways and expression of specific transcription factors, notably T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for T-regs and receptor-related orphan receptor (ROR)alpha and ROR gamma t for Th17 cells. T-regs and Th17 cells have been demonstrated to arise from common precursors in a reciprocal manner based on exposure to transforming growth factor (TGF)-beta or TGF-beta plus interleukin (IL)-6 and carry out diametrically opposing functions, namely suppression or propagation of inflammation, respectively. However, while epigenetic modifications in Th1 and Th2 differentiated cells prevents their conversion to other phenotypes, Th17 cells generated in vitro using TGF-beta and IL-6 are unstable and can convert to other phenotypes, especially Th1, both in vitro and in vivo. T-regs are generated from naive precursors both in the thymus (natural, nT(regs)) and in the periphery (induced, iT(regs)). The highly suppressive function of T-regs enables them to control many inflammatory diseases in animals and makes them particularly attractive candidates for immunotherapy in humans. The stability of the T-reg phenotype is therefore of paramount importance in this context. Recent descriptions of T-reg biology have suggested that components of pathogens or inflammatory mediators may subvert the suppressive function of T-regs in order to allow propagation of adequate immune responses. Unexpectedly, however, a number of groups have now described conversion of T-regs to the Th17 phenotype induced by appropriate inflammatory stimuli. These observations are particularly relevant in the context of cell therapy but may also explain some of the dysregulation seen in autoimmune diseases. In this paper, we review T-reg to Th17 conversion and propose some potential mechanisms for this phenomenon.