Signal transduction and Th17 cell differentiation

Abstract

The paradigm of effector T helper cell differentiation into either Th1 or Th2 lineages has been notably shaken by the discovery of a third lineage of cells that selectively produce interleukin (IL)-17. Characterization of this new subset, referred to as Th17, has provided exciting new insights into immunoregulation, host defense and the pathogenesis of autoimmune diseases. Additionally, the discovery of this T cell subset has offered a fresh look at such concepts as lineage commitment and terminal differentiation. The transcriptional regulatory events and epigenetic modifications that control these processes are diverse and complex, and despite the rapid pace at which data continue to accumulate, many questions remain to be answered. Here we review our current understanding of the signaling pathways, molecular interactions and transcriptional events that lead to Th17 differentiation and effector function, as well as the epigenetic modifications that accompany them.

Fig 1. Jak/STAT targets of cytokines involved in T helper cell differentiation

The receptors of Type I and Type II cytokines associate with Janus kinases (Jaks). Cytokine binding activates the Jaks, which phosphorylate the receptors, allowing the recruitment of signal transducers and activators of transcription (STATs). Recruited STATs are phosphorylated and subsequently form dimers. STAT dimers translocate to the nucleus, where they regulate gene expression. Many cytokines are known to activate more than one STAT pair. The receptor components and downstream Jak/STAT targets of IL-2, IL-4, IL-6, IL-12, IL-21 and IL-23 are diagrammed above. Major and minor signaling pathways are represented with solid and dashed arrows respectively.

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

In helper T cells, TCR stimulation activates NFAT, which is thought to directly regulate IL-17 expression. Cytokines such as IL-6, IL-21 and IL-23 activate STAT3, which in turn binds the IL17A, IL17F and IL21 genes. STAT3 is also thought to regulate RORγt expression and is inhibited by the cytokine inducible Socs3. Although uncertain, IRF4 is thought to co-operate with STAT3 to induce RORyt expression. TGF-β1 signaling involves the activation of SMAD proteins, although the mechanism by which it promotes both iTreg and Th17 differentiation remains unknown. The mechanism by which IL-1 signaling via MyD88 promotes Th17 differentiation is also unknown; one possibility is via NF-κB. RORγt and RORα regulation of IL-17 production is poorly understood, although RORγt has been found to bind the Il17A gene. Binding of the AHR ligand FICZ causes dissociation of the receptor with cytoplasmic chaperones, enabling it to translocate to the nucleus, heterodimerize and promote IL-17 and IL-22 expression. Discouraging Th17 differentiation, IL-2, IL-4, IL-27 and IFN-γ inhibit STAT 3 activity through STATs 5,6 and 1 respectively. Notably, STAT5 also regulates Foxp3 expression. RA, acting through its cognate receptors, downregulates RORyt expression and up-regulates Foxp3 expression. Runx1 associates with both RORγt and Foxp3 and possibly regulates differentiation towards either the iTreg or Th17 lineage. Abbreviations: AHR. aryl hydrocarbon receptor; ARNT. Aryl receptor nuclear translocator; Co-SMAD. Co-mediator SMAD; FICZ. 6-formylindolo[3,2-b] carbazole; R-SMAD. receptor-regulated SMAD; RA(R). retinoic acid (receptor)