In addition to their well-characterized role in immune pathology, T helper 17 (TH17) cells maintain homeostasis at barrier sites by containing commensal bacteria, inducing the expression of tight junction proteins and antimicrobial peptides, and fighting pathogens.
Segmented filamentous bacteria (SFB) are the main drivers of the differentiation of intestinal TH17 cells, which in turn control SFB burden through interleukin-17 (IL-17) signalling in intestinal epithelial cells.
The substantial degree of plasticity displayed by TH17 cells is context-dependent and can be beneficial (for example, having an intestinal regulatory function or promoting IgA production) or pathogenic (for example, inducing the production of additional pro-inflammatory cytokines during central nervous system inflammation).
A multitude of environmental factors — including diet, aryl hydrocarbon receptor ligands, circadian rhythms and the microbiota — influence the function of TH17 cells.
When targeting TH17 cells in inflammatory diseases, we need to ensure that the protective functions of intestinal TH17 cells are not compromised.
T helper 17 (TH17) cells have been extensively studied since their discovery 10 years ago, primarily because of their known pathogenic role in many inflammatory diseases. Substantial progress has been made in understanding their development, regulation and functional activities, and genome-wide transcriptomic analysis has identified regulatory networks, nodes and interactions that provide vital clues for further studies. In this Review, we describe recent studies that have revealed the dichotomous nature of TH17 cells, which on the one hand allows these cells to be pathogenic drivers of inflammatory disorders and on the other hand allows them to support the integrity of the intestinal barrier in a non-inflammatory manner.
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The authors declare no competing financial interests.
- Inflammatory bowel disease
(IBD). A chronic inflammatory condition that affects the intestinal tract. The proposed pathogenesis of IBD involves a complex model that includes functional abnormalities of innate immune cells and their relationship with the commensal microbiota; the inappropriate release of pro-inflammatory cytokines and other mediators; alterations of the intestinal epithelial barrier; and a cytokine imbalance that promotes the pro-inflammatory activity of adaptive immune cells.
(miRNAs). Small RNA molecules that regulate the expression of genes by binding to the 3′ untranslated regions of specific mRNAs.
- Cell fate reporter mice
Mice in which the mapping of cell fates is based on two genetically engineered alleles that express a site-specific recombinase and a reporter allele that permanently expresses a marker following site-specific recombination. Cells that express the reporter are permanently marked with the fluorescent protein irrespective of subsequent changes to expression of the Cre recombinase-targeted gene.
- Transfer model of colitis
A mouse model of T cell-mediated pan-colitis and small bowel inflammation that is induced by the adoptive transfer of naive CD4+ T cells into syngeneic recipients that lack T cells and B cells.
- T follicular helper cells
(TFH cells). CD4+ T cells that provide help to B cells in follicles and germinal centres. The TFH cell signature includes the expression of CXC-chemokine receptor 5, inducible T cell co-stimulator, CD40 ligand and interleukin-21, which mediate TFH cell homing to follicles and B cell help.
- Peyer's patches
Groups of lymphoid nodules present in the small intestine that are massed together on the intestinal wall, opposite to the line of attachment of the mesentery. Peyer's patches consist of a subepithelial dome area, B cell follicles and interfollicular T cell zones.
- Activation-induced cytidine deaminase
An enzyme that is required for two crucial events in the germinal centre: somatic hypermutation and class-switch recombination.
- T regulatory type 1-like cells
(TR1-like cells). A subset of CD4+ regulatory T cells that secrete high levels of interleukin-10 (IL-10), and downregulate T helper 1 (TH1) and TH2 cell responses in vitro and in vivo by a contact-independent mechanism that is mediated by the secretion of soluble IL-10 and transforming growth factor-β.
- Group 3 innate lymphoid cells
(ILC3s). A subset of innate lymphoid cells that express RORγt. They can be further subdivided into CC-chemokine receptor 6 (CCR6)-expressing ILC3s, which are present at birth and produce both interleukin-17 (IL-17) and IL-22, and postnatal CCR6− ILC3s, which produce only IL-22. ILC3s are required for the development of intestinal cryptopatches and isolated lymphoid follicles, and are crucial for the maintenance of mucosal barriers, as they are the main source of homeostatic IL-22.
A condition in which the balance of the bacterial communities that constitute the intestinal microbiota is altered; this condition could represent a predisposing factor for several diseases.
- Dextran sodium sulfate
(DSS). A large polysaccharide that causes epithelial injury and inflammation in the intestinal tract, and is commonly used in models of experimentally induced colitis, which are used to study the response to intestinal injury.
- Physiological hypoxia
A setting that does not result in any pathology and in which the partial oxygen pressure is decreased owing to organ-specific rates of vascularization.
- Tight junction
A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight junction proteins include the integral membrane proteins occludin and claudin, which associate with cytoplasmic zonula occludens proteins.
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Stockinger, B., Omenetti, S. The dichotomous nature of T helper 17 cells. Nat Rev Immunol 17, 535–544 (2017). https://doi.org/10.1038/nri.2017.50
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