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The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing

Nature Reviews Immunology volume 14, pages 585–600 (2014)Cite this article

Subjects

Key Points

  • T helper 17 (TH17) cells activated by transforming growth factor-β (TGFβ) and interleukin-6 (IL-6) promote mucosal defence, barrier tissue integrity and curtail immunopathogenic responses, whereas IL-23-activated TH17 cells promote chronic tissue inflammation during infection, granuloma formation and autoimmunity.

  • Retinoic acid receptor-related orphan receptor-γt (RORγt) is a TH17 cell-specific master transcription factor. However, it does not act alone, but instead functions as part of a protein complex that regulates TH17 lineage fate. RORγt takes advantage of the open DNA conformation induced by basic leucine zipper transcription factor ATF-like (BATF) and interferon-regulatory factor 4 (IRF4) following T cell receptor stimulation. RORγt also requires the presence of inflammatory cytokine-induced signal transducer and activator of transcription 3 (STAT3) and, together, these transcription factors function as a 'rheostat' that fine-tunes a pre-established TH17 lineage programme.

  • IL-17 signalling is mediated through a distinct cytokine receptor family, which is characterized by a conserved SEF/IL-17R (SEFIR) domain in the cytoplasmic tail. All known IL-17-dependent signalling events occur through ACT1, which controls TNF receptor-associated factor (TRAF)-dependent activation of downstream signalling components (for example, mitogen-activated protein kinases) and transcription factors (for example, nuclear factor-κB (NF-κB) and CCAAT/enhancer-binding proteins (C/EBPs) and mRNA stability.

  • IL-17 signal transduction is restricted by multiple downstream events, involving inhibitory transcription factors, ubiquitylation/deubiquitylation of signalling intermediates, microRNA regulation and control of target mRNA stability.

  • In vivo, IL-17 is an essential regulator of immunity to fungi, particularly the commensal fungus Candida albicans. Humans with congenic or acquired blockade of the IL-17 signalling pathway are particularly susceptible to chronic mucosal candidiasis.

  • The therapeutic strategy of targeting IL-17 and IL-23 shows encouraging results for psoriasis, Crohn's disease, rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

Abstract

Following the discovery of T helper 17 (TH17) cells, the past decade has witnessed a major revision of the TH subset paradigm and substantial progress has been made in deciphering the molecular mechanisms of T cell lineage commitment and function. In this Review, we focus on the recent advances that have been made regarding the transcriptional control of TH17 cell plasticity and stability, as well as the effector functions of TH17 cells, and we highlight the mechanisms of IL-17 signalling in mesenchymal and barrier epithelial tissues. We also discuss the emerging clinical data showing that IL-17-specific and IL-23-specific antibody treatments are remarkably effective for treating many immune-mediated inflammatory diseases.

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Figure 1: Timeline of the discovery and elucidation of IL-17 and IL-23 biology
Figure 2: Schematics of transcription factor regulation for TH17 cell lineage specification and function.
Figure 3: IL-17 ligand and receptor family members.
Figure 4: IL-17 receptor signal transduction.

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Acknowledgements

S.L.G. was supported by US National Institutes of Health (NIH) grants AI107825 and DE022550. The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Division of Rheumatology and Clinical Immunology, S702 BST, 3500 Terrace Street, Pittsburgh, 15261, Pennsylvania, USA

    Sarah L. Gaffen & Abhishek V. Garg

  2. Merck Research Laboratories, Palo Alto, 901 California Avenue, Palo Alto, 94304, California, USA

    Renu Jain & Daniel J. Cua

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S.L.G. has received research grants from Novartis and Janssen, and has consulted for and received travel reimbursements and/or honouraria from Novartis, Amgen, Pfizer, Eli Lilly and Janssen. R.J. and D.J.C. are employed by Merck and Co. A.V.G. declares no competing interests.

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FURTHER INFORMATION

ClinicalTrials.gov

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Supplementary information

Supplementary information S1 (table)

Summary of phase II clinical trials of clinical testing of anti-interleukin-23 (IL-23) and anti-IL-17 treatment for psoriasis (PDF 616 kb)

Glossary

Crohn's disease

A type of inflammatory bowel disease that affects any part of the gastrointestinal tract from the mouth to the anus. Symptoms include abdominal pain, bloody diarrhoea, fever and weight loss. Other complications may occur outside the gastrointestinal tract and include anaemia, skin rashes, arthritis, inflammation of the eye and an increased risk of bowel cancer.

Chromatin immunoprecipitation followed by sequencing

(ChIP–seq). A technique used to analyse the interactions between transcription factors and their target DNA. ChIP–seq combines chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing to identify the specific sequences bound by regulatory proteins.

Hyper-IgE syndrome

An inherited immune deficiency that is usually caused by mutations in signal transducer and activator of transcription 3 (STAT3) and is associated with reduced T helper 17 (TH17) cell frequency. The disease is characterized by elevated levels of serum IgE, eosinophilia, 'cold' staphylococcal abscesses, eczema, pulmonary infections and chronic mucocutaneous candidiasis.

Antimicrobial peptides

Short peptides (typically 12–50 amino acids) with bactericidal and fungicidal activities. Some may also exhibit chemotactic activities.

A20

The product of the tumour necrosis factor-α-induced protein 3 (TNFAIP3) gene. This is a zinc finger-containing protein with E3 ligase and deubiquitylase activity that downregulates signalling by multiple inflammatory effectors.

microRNAs

(miRNAs). Single-stranded RNA molecules of approximately 21–23 nucleotides in length that regulate gene expression.

Autoimmune polyendocrinopathy syndrome 1

(APS1; also known as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome). An inherited autoimmune disorder that affects multiple endocrine tissues and is caused by mutations in the autoimmune regulator (AIRE) gene. The disease is associated with a high incidence of mucocutaneous candidiasis, which is thought to be owing to neutralizing autoantibodies against interleukin-17A (IL-17A), IL-17F and/or IL-22.

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Gaffen, S., Jain, R., Garg, A. et al. The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 14, 585–600 (2014). https://doi.org/10.1038/nri3707

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