Editors' ChoiceAutoimmunity

A cytokine duet regulates inflammatory bowel disease

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Science Translational Medicine  18 Jul 2018:
Vol. 10, Issue 450, eaau4583
DOI: 10.1126/scitranslmed.aau4583

Abstract

Inhibition of IL-17F, but not IL-17A, promotes microbiota-mediated regulatory T cell generation in the colon and ameliorates intestinal inflammation in mice.

Interleukin 17-A (IL-17A) is a key proinflammatory cytokine that contributes to several autoimmune diseases. However, treatment of inflammatory bowel diseases (IBD) utilizing anti–IL-17A was not successful and sometimes exacerbated symptoms in clinical trials. IL-17A has a close cousin, IL-17F. The genes encoding both cytokines share high similarity. T cells are known to be involved in IBD, and they produce both cytokines. In the intestine, IL-17A is primarily produced by activated T cells. In contrast, IL-17F is constitutively produced by all types of intestinal cells, including T cells, natural killer cells, dendritic cells, and epithelial cells. How IL-17F contributes to IBD remains largely unknown.

Tang and colleagues addressed this question using different colitis models in mice deficient for IL-17A, IL-17F, or both cytokines. Their data showed that whereas IL-17A deficiency led to colitis with similar or worse pathology than controls, IL-17F or IL-17A/IL-17F deficiency protected against colitis symptoms. Protection was associated with increased intestinal regulatory T cell (Treg) frequency. The Treg expansion was induced by overcolonization of Treg-promoting commensal bacteria, Clostridium cluster XIVa (C. XIVa) and Lactobacillus murinus. Mice with colitis had elevated constitutive IL-17F production in the intestine compared with healthy mice. IL-17F induced production of certain antimicrobial peptides that suppressed C. XIVa and L. murinus. Furthermore, IL-17F produced by both T cells and non–T cells contributed to the colitis pathology. Importantly, treatment with anti–IL-17F antibody, but not anti–IL-17A antibody, reduced severity of symptoms.

In most cases, IL-17A plays a dominant role, whereas IL-17F serves a marginal but similar function. This study illustrates the context-dependent functions of two closely related cytokines. In the intestine, these cytokines have opposite functions, and IL-17F dominates IL-17A to promote inflammation. The rising incidence of IBD globally necessitates new targeted therapy. Although this study was carried out in animal models, it provides mechanistic rationale to target IL-17F or IL-17F–regulated microbiota for the treatment of IBD in future clinical studies.

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