Recent advances in the IL-17 cytokine family

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The IL-17/IL-17 receptor family is the newest and least understood of the cytokine subclasses. Composed of ligands IL-17A-IL-17F and receptors IL-17RA-IL-17RE, these cytokines have many unique structural and functional features. Since the discovery of the ‘Th17’ subset in 2005, particular attention has been paid to IL-17A and IL-17F and their cognate receptors. To date, far less is known about the rest of the family. This review discusses recent advances in the field, with an emphasis on IL-17A biology.

Highlights

► IL-17, signature of the CD4+ ‘Th17’ lineage, is also produced by innate cell types. ► il17a gene regulation and epigenetics helps explain Th cell plasticity. ► Data from animal models and humans reveal a vital role of IL-17 in fungal immunity. ► Anti-IL-17 therapeutics show early promise in the clinic. ► The IL-17 receptor activates noncanonical signal transduction pathways.

Section snippets

IL-17-producing cells: Th17 and beyond

IL-17 (IL-17A, CTLA-8, Table 1) was cloned in 1993, but came into the limelight with the recognition of a third effector CD4+ T cell population distinct from classic Th1 and Th2 lineages, which produces IL-17 as a signature cytokine and responds potently to IL-23. Dubbed ‘Th17,’ IL-17-producing CD4+ cells arise from multiple differentiation triggers, including TGFβ, IL-6, IL-1β, and IL-21 (Figure 1a). IL-23 is not required for Th17 differentiation per se, but is essential for maintenance and

Interconnections among T cell subsets

Although Th17 cells are often depicted as a committed lineage, in fact there are many interrelationships with other subpopulations, including functional cooperation, cells that express signature cytokines from multiple subsets (e.g. IL-17 + IFNγ+ cells) and lineage plasticity. For example, Th17 cells and Tregs both arise from TGFβ-dependent signals, although the importance of TGFβ in Th17 generation continues to be controversial [8, 9, 10]. Th17 cells can convert to Tregs and vice versa or

IL-17 gene regulation

The genes encoding IL-17A and IL-17F are closely linked, and a comprehensive picture of gene regulation is starting to emerge [28] (Figure 1b). Within the intergenic DNA between il17a and il17f lies a conserved noncoding sequence region. The chromatin in this locus is extensively remodelled upon receipt of signals from TGFβ and IL-6, helping to explain coordinate regulation of these cytokines [29]. Early studies demonstrated the importance of NFATc1 in regulating the human IL-17A promoter,

IL-17 in fungal infections

Numerous studies identified a role for IL-17 in immunity against extracellular pathogens [5]. In particular, several new reports implicate IL-17 as a particularly vital mediator of host defense against fungi. Candida albicans is an opportunistic yeast that colonizes skin and mucosal tissues, and can cause systemic infections that are a serious problem in hospitals. In mice, deficiency of IL-17A and IL-17RA but not IL-17F causes increased susceptibility to disseminated candidiasis [41, 42].

IL-17 in autoimmunity, therapies

Even before the discovery of Th17 cells, it was evident that IL-17 promotes autoimmunity, particularly in the context of rheumatoid arthritis (RA) [59]. Analyses of collagen-induced arthritis (CIA) confirmed that Th17 cells rather than Th1 cells promote disease [60], and blocking IL-17 or its receptor relieves experimental symptoms [61]. Studies in EAE similarly indicated a dominant role of Th17 cells over Th1 cells [62]. In humans, a SNP in the IL-23R (R381Q) is associated with reduced

IL-17 receptor structure and signaling

The receptor for IL-17A, IL-17F and the IL-17A/F heterodimer is composed of IL-17RA paired with IL-17RC [4]. The crystal structure of the human IL-17RA extracellular domain complexed to an IL-17F:F homodimer reveals an unusual fibronectin III domain conformation [67••]. Surface plasmon resonance studies showed stepwise association of receptor/ligand binding; namely, after either IL-17RA or IL-17RC bind their respective ligand, affinity for the reciprocal subunit is increased. This observation

Summary and perspectives

The recognition of Th17 cells has stimulated a surge of interest in IL-17 cytokines. Although much remains to be learned about this enigmatic family, intensive studies in mice have provided much new information about this cytokine and its fascinating cellular and molecular regulation. The advent of clinical trials targeting IL-17 and its receptor will no doubt shed new light on its biology in humans as well.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

SLG was supported by National Institutes of Health grant AR054389. We thank S. Christakos (UMDNJ, Newark NJ) for critical reading, and Dr. Tom Hamilton (Cleveland Clinic, Cleveland OH) for sharing unpublished information.

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