Interleukin-17 (IL-17; also known as IL-17A), the hallmark cytokine of the newly-defined T helper 17 (TH17) cell subset has important roles in protecting the host against extracellular pathogens, but conversely promotes inflammatory pathology in autoimmune disease. IL-17A and its receptor (IL-17RA) are the founding members of a new subfamily of cytokines/receptors, with unique structural features that distinguish them from other cytokine subclasses. Research defining the signal transduction pathways mediated by IL-17-family cytokines has lagged behind other receptors, but studies in the past 2 years have begun to delineate unusual functional motifs and novel proximal signaling mediators used by the IL-17R family to mediate downstream events.
In 1986, a seminal paper by Coffman and Mosman postulated the existence of subsets of T helper (TH) cells characterized by differential secretion of cytokines, designated TH1 and TH2 cells [G] 1. Although this viewpoint dominated for nearly 2 decades 2, discrepancies arose as details of TH cell development became more refined. In particular, deficiency of interleukin-12 (IL-12) (specifically, the IL-12p40 subunit of this heterodimeric cytokine), which drives the TH1 cell lineage, frequently failed to phenocopy deficiency of interferon-γ (IFNγ), the hallmark TH1 cell cytokine 3. The basis for this paradox became evident when it was recognized that IL-12p40 is also a constituent of IL-23 (together with IL-23p19), and so IL-12p40-deficient mice lack both IL-12 and IL-23 4. Further studies showed that IL-23 stimulates IL-17A production in a subset of CD4+ T cells 5, 6, and IL-23p19-deficient mice but not IL-12p35-deficient mice are susceptible to certain autoimmune diseases 7. This revealed a new branch of the TH cell family tree, now known as TH17 cells [G] (TIMELINE).
Numerous reports rapidly followed, describing the factors involved in differentiation of this lineage, the additional cytokines produced by TH17 cells, and the production of TH17-type cytokines by other cell types. To summarize briefly, TH17 cells are driven to differentiate by transforming growth factor-β (TGFβ), IL-1, and IL-6, and IL-23 is required to expand and stabilize the population. The transcription factors signal transducer and activator of transcription 3 (STAT3), retinoic acid receptor-related orphan receptor-γt (RORγt) and AHR (aryl hydrocarbon receptor) control TH17 cell differentiation. In addition to IL-17, TH17 cells produce IL-17F (this cytokine is discussed in subsequent sections), IL-21, IL-22 and IL-26, as well as chemokines including CCL20/MIP3α. TH17 cells function prominently at mucosal surfaces, and trigger pro-inflammatory “danger” signals that promote neutrophil mobilization and the expression of anti-microbial factors. Conversely, TH17 cells drive inflammatory pathology in various autoimmune conditions. Finally, various “TH17-like“ cells exist, which produce a similar array of cytokines; these include γδ T cells [G], natural killer (NK) cells and NKT cells, and LTi (lymphoid tissue inducer) [G] cells. The reader is referred to several excellent reviews on this topic 8-10.
Less attention has been paid to the mechanisms by which IL-17 family cytokines mediate effects at a molecular level. IL-17A and its receptor are founding members of a new subfamily of cytokines (IL-17A-F) and receptors (IL-17RA-RE) (Table 1). The IL-17R family has unique structural features and mediates signalling events that are surprisingly distinct from other cytokines, particularly those usually involved in adaptive immunity. Whereas the signature cytokines involved in the TH1 and TH2 cell lineages trigger JAK–STAT signalling pathways, IL-17-family cytokines mediate signalling through a novel ACT1-dependent pathway, culminating in the activation of pro-inflammatory factors such as NF-κB that are usually associated with innate immune signalling (Box 1). So, by virtue of the unusual signalling properties of IL-17, TH17 cells act as a bridge between adaptive and innate immunity 11. Recent work has begun to define the architecture of the IL-17 family, and its sometimes surprising ligand–receptor relationships and signal transduction pathways. This article reviews recent discoveries in this field in the context of cytokine receptor biology as well as the potential implications of this knowledge with respect to emerging therapeutics.
Box 1. IL-17R signalling is a bridge between adaptive and innate immunity
Traditional TH1 and TH2 signature cytokines signal through JAK-STAT-mediated pathways, with IFNγ activating a JAK1/2-STAT1-dependent pathway and IL-4 activating a JAK1/3- STAT6-dependent pathway. Activation of these pathways is critical both for the effector functions of these cells but also for their development. In contrast, IL-17A and IL-17F derived from TH17 cells promote ACT1/TRAF6/NF-κB-dependent signalling, which is much more reminiscent of receptors associated with innate immunity, such as IL-1-family receptors and TLR ligands. Interestingly, another TH17 hallmark cytokine is IL-22, which activates a JAK-STAT3 signalling programme, but the downstream gene targets are strikingly similar to genes induced by IL-17. Thus, TH17 cells promote signals typical of early inflammatory events, and in this sense serve to bridge innate and adaptive immune processes.