Translational mini-review series on Th17 cells: induction of interleukin-17 production by regulatory T cells

Abstract

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 RORgammat 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.

Fig. 1

Regulatory T cells during infection. In the context of infection, excessive regulatory T cell (T_reg) activity may leave the host susceptible to overwhelming infection (left side of the swing), while too little T_reg activity may result in excessive tissue injury from unbridled inflammation (right side of the swing).

Fig. 2

The Janus kinase/signal transducer and activator of transcription/suppressor of cytokine signalling (JAK/STAT/SOCS) axis. Cytokine engagement of their cognate receptors (a) leads to receptor dimerization, which activates JAK kinases. Activated JAKs phosphorylate the cytoplasmic tails of the receptor (b), creating docking sites for Src-homology-2 (SH2)-domain-containing proteins such as STATs (c). Docked STATs are activated by JAKs, dissociate from the receptor and dimerize (d). Dimerized STATs migrate to the nucleus and associate with specific STAT binding sites (e) and (positively or negatively) regulate expression of STAT-responsive genes, including suppressor of cytokine signalling (SOCS) proteins. SOCS proteins also contain an SH2-domain and feed back to inhibit this pathway through competition with STAT proteins for SH2-domain-docking sites (f), SH2-recruitment to the receptor cytoplasmic domain followed by JAK inhibition (g) or direct inhibition of JAK activity (h). In addition, SOCS proteins contain a SOCS box motif which contains an E3 ubiquitin–ligase complex, through which the SOCS protein can ubiquitinate JAK proteins and target them for proteosomal degradation (i).