Signal transduction pathways and transcriptional regulation in Th17 cell differentiation

Abstract

Over the last decade, our understanding of helper/effector T cell differentiation has changed dramatically. The discovery of interleukin (IL-)17-producing T cells (Th17) and other subsets has changed our view of T cell-mediated immunity. Characterization of the signaling pathways involved in the Th17 commitment has provided exciting new insights into the differentiation of CD4+ T cells. Importantly, the emerging data on conversion among polarized T helper cells have raised the question how we should view such concepts as T cell lineage commitment, terminal differentiation and plasticity. In this review, we will discuss the current understanding of the signaling pathways, molecular interactions, and transcriptional and epigenetic events that contribute to Th17 differentiation and acquisition of effector functions.

Fig 1. STAT3, p300, BATF and RORγt binding sites in the Il17/Il17f locus

In addition to the previous identified STAT3 binding sites in the promoters of Il17 and Il17f in Th17 conditions [77], STAT3 have been found to bind strongly with multiple conserved non-coding sequences located in the intergenic region between Il17 and Il17f [82]. Binding sites of p300 has been found in this locus by our study [60]. Binding sites of BATF and RORγt has been reported by others [100] [97]. The significance of those individual binding sites is of interest for further investigations.

Fig 2. Signaling pathways and transcription factors that regulate Th17 differentiation

TCR stimulation activates the transcription factor NFAT, which regulates IL-17 and IL-17F differentially. IL-6, IL-21 and IL-23 induce STAT3 activation, which in turn binds the Il17, I17f and Il21 genes. STAT3 binds to Rorc and Irf4 genes and IRF4 co-operates with STAT3 to induce RORγt expression. TGF-β1 signaling involves the activation of SMAD proteins, although the mechanism by which it promotes both iTreg and Th17 differentiation remains largely unknown. One possibility is that it does not provide inductive signals, but only attenuates expression of T-bet, GATA3 and other factors. IL-1 signals to potentiate IL-6-induced IRF4 expression thus promotes Th17 differentiation. Both RORγt and RORα bind the Il17 gene. In contrast, IL-2, IL-4, IL-27 and IFN-γ inhibit Th17 differentiation through STAT5, STAT6 and STAT1 activation respectively, although the underlying mechanism(s) are not completely understood. Reciprocally, STAT5 upregulates Foxp3 expression. Runx1 associates with both RORγt and Foxp3 and possibly regulates differentiation towards either the iTreg or Th17 lineage. Cytokines also upregulate Socs3, which attenuates STAT3 activation.