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Since their discovery almost two decades ago, interleukin-17-producing CD4 + T cells (T H 17 cells) have been implicated in the pathogenesis of multiple autoimmune and inflammatory disorders. In addition, T H 17 cells have been found to play an important role in tissue homeostasis, especially in the intestinal mucosa. Recently, the use of single-cell technologies, along with fate mapping and various mutant mouse models, has led to substantial progress in the understanding of T H 17 cell heterogeneity in tissues and of T H 17 cell plasticity leading to alternative T cell states and differing functions. In this Review, we discuss the heterogeneity of T H 17 cells and the role of this heterogeneity in diverse functions of T H 17 cells from homeostasis to tissue inflammation. In addition, we discuss T H 17 cell plasticity and its incorporation into the current understanding of T cell subsets and alternative views on the role of T H 17 cells in autoimmune and inflammatory diseases. Kuchroo and colleagues review T H 17 cell heterogeneity and discuss how this affects the function of T H 17 cells in homeostasis and disease.

A defining feature of adaptive immunity is the development of long-lived memory T cells to curtail infection. Recent studies have identified a unique stem-like T-cell subset amongst exhausted CD8-positive T cells in chronic infection 1 – 3 , but it remains unclear whether CD4-positive T-cell subsets with similar features exist in chronic inflammatory conditions. Amongst helper T cells, T H 17 cells have prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity 4 – 7 , although how such plasticity is regulated is poorly understood. Here we demonstrate that T H 17 cells in a mouse model of autoimmune disease are functionally and metabolically heterogeneous; they contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports transdifferentiation into T H 1-like cells. These two T H 17-cell subsets are defined by selective expression of the transcription factors TCF-1 and T-bet, and by discrete levels of CD27 expression. We also identify signalling via the kinase complex mTORC1 as a central regulator of T H 17-cell fate decisions by coordinating metabolic and transcriptional programmes. T H 17 cells with disrupted mTORC1 signalling or anabolic metabolism fail to induce autoimmune neuroinflammation or to develop into T H 1-like cells, but instead upregulate TCF-1 expression and acquire stemness-associated features. Single-cell RNA sequencing and experimental validation reveal heterogeneity in fate-mapped T H 17 cells, and a developmental arrest in the T H 1 transdifferentiation trajectory upon loss of mTORC1 activity or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous T H 17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of plasticity in helper T cells. Phenotypically, transcriptionally and metabolically diverse subsets of T H 17 cells develop in a chronic autoimmune disease: one subset has inferred stemness features and low anabolic metabolism, while a reciprocal subset has higher metabolic activity that supports transdifferentiation into T H 1 cells.

Krönke and colleagues show that the cytokine IL-23 controls the glycosylation profile and inflammatory activity of autoantibodies through control of sialyltransferase activity in plasma cells mediated by the T H 17 subset of helper T cells. The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the T H 17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, T H 17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23–T H 17 cell–dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.

Neutrophils perform critical functions in the innate response to infection, including through the production of neutrophil extracellular traps (NETs) - web-like DNA structures which are extruded from neutrophils upon activation. Elevated levels of NETs have been linked to autoimmunity but this association is poorly understood. By contrast, IL-17 producing Th17 cells are a key player in various autoimmune diseases but are also crucial for immunity against fungal and bacterial infections. Here we show that NETs, through their protein component histones, directly activate T cells and specifically enhance Th17 cell differentiation. This modulatory role of neutrophils, NETs and their histones is mediated downstream of TLR2 in T cells, resulting in phosphorylation of STAT3. The innate stimulation of a specific adaptive immune cell subset provides an additional mechanism demonstrating a direct link between neutrophils, NETs and T cell autoimmunity. Neutrophils are critical in the immune response to infective agents and have multiple effector strategies including the production of extracellular traps termed NETs. Here the authors show a link between NET production and Th17 differentiation which mechanistically occurs downstream of TLR2 signalling.

Periodontitis is closely related to inflammatory bowel disease (IBD). An excessive and non-self-limiting immune response to the dysbiotic microbiome characterizes the two. However, the underlying mechanisms that overlap still need to be clarified. We demonstrate that the critical periodontal pathogen Porphyromonas gingivalis (Pg) aggravates intestinal inflammation and Th17/Treg cell imbalance in a gut microbiota-dependent manner. Specifically, metagenomic and metabolomic analyses shows that oral administration of Pg increases levels of the Bacteroides phylum but decreases levels of the Firmicutes , Verrucomicrobia , and Actinobacteria phyla. Nevertheless, it suppresses the linoleic acid (LA) pathway in the gut microbiota, which was the target metabolite that determines the degree of inflammation and functions as an aryl hydrocarbon receptor (AHR) ligand to suppress Th17 differentiation while promoting Treg cell differentiation via the phosphorylation of Stat1 at Ser727. Therapeutically restoring LA levels in colitis mice challenged with Pg exerts anti-colitis effects by decreasing the Th17/Treg cell ratio in an AHR-dependent manner. Our study suggests that Pg aggravates colitis via a gut microbiota-LA metabolism-Th17/Treg cell balance axis, providing a potential therapeutically modifiable target for IBD patients with periodontitis. Periodontitis is closely linked with inflammatory bowel disease (IBD) and may have overlapping characteristics. Here the authors show that a periodontal pathogen P. gingivalis promotes intestinal inflammation by affecting the microbiome metabolite linoleic acid and Th17/Treg cell balance in the intestine.

A mounting body of evidence indicates that dietary fiber (DF) metabolites produced by commensal bacteria play essential roles in balancing the immune system. DF, considered nonessential nutrients in the past, is now considered to be necessary to maintain adequate levels of immunity and suppress inflammatory and allergic responses. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are the major DF metabolites and mostly produced by specialized commensal bacteria that are capable of breaking down DF into simpler saccharides and further metabolizing the saccharides into SCFAs. SCFAs act on many cell types to regulate a number of important biological processes, including host metabolism, intestinal functions, and immunity system. This review specifically highlights the regulatory functions of DF and SCFAs in the immune system with a focus on major innate and adaptive lymphocytes. Current information regarding how SCFAs regulate innate lymphoid cells, T helper cells, cytotoxic T cells, and B cells and how these functions impact immunity, inflammation, and allergic responses are discussed.

Key Points T helper 17 (T H 17) 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 T H 17 cells promote chronic tissue inflammation during infection, granuloma formation and autoimmunity. Retinoic acid receptor-related orphan receptor-γt (RORγt) is a T H 17 cell-specific master transcription factor. However, it does not act alone, but instead functions as part of a protein complex that regulates T H 17 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 T H 17 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. T helper 17 (T H 17) cells promote protective immune responses against infection, particularly at barrier sites, but they can also have pathogenic roles in inflammatory diseases. In this Review, the authors describe the factors that control the development and maintenance of T H 17 cells, and discuss their diverse functions in both health and disease. Following the discovery of T helper 17 (T H 17) cells, the past decade has witnessed a major revision of the T H 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 T H 17 cell plasticity and stability, as well as the effector functions of T H 17 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.

Short-chain fatty acids (SCFAs) have immunomodulatory effects, but the underlying mechanisms are not well understood. Here we show that pentanoate, a physiologically abundant SCFA, is a potent regulator of immunometabolism. Pentanoate induces IL-10 production in lymphocytes by reprogramming their metabolic activity towards elevated glucose oxidation. Mechanistically, this reprogramming is mediated by supplying additional pentanoate-originated acetyl-CoA for histone acetyltransferases, and by pentanoate-triggered enhancement of mTOR activity. In experimental mouse models of colitis and multiple sclerosis, pentanoate-induced regulatory B cells mediate protection from autoimmune pathology. Additionally, pentanoate shows a potent histone deacetylase-inhibitory activity in CD4 + T cells, thereby reducing their IL-17A production. In germ-free mice mono-colonized with segmented filamentous bacteria (SFB), pentanoate inhibits the generation of small-intestinal Th17 cells and ameliorates SFB-promoted inflammation in the central nervous system. Taken together, by enhancing IL-10 production and suppressing Th17 cells, the SCFA pentanoate might be of therapeutic relevance for inflammatory and autoimmune diseases. Short-chain fatty acids (SCFAs) have immunomodulatory effects, but the underlying mechanisms are still unclear. Here the authors show that a SCFA, pentanoate, suppresses autoimmune inflammation in mouse models of colitis and multiple sclerosis via epigenetic modulation of immune cell metabolic and functional pathways.

Smoking can lead to emphysema. Corry and colleagues show that smoke and carbon black particles induce the microRNA miR-22 as a mediator that suppresses expression of the histone deacetylase HDAC4 and thereby promotes a chronic T H 17 cell–dependent inflammatory response. Smoking-related emphysema is a chronic inflammatory disease driven by the T H 17 subset of helper T cells through molecular mechanisms that remain obscure. Here we explored the role of the microRNA miR-22 in emphysema. We found that miR-22 was upregulated in lung myeloid dendritic cells (mDCs) of smokers with emphysema and antigen-presenting cells (APCs) of mice exposed to smoke or nanoparticulate carbon black (nCB) through a mechanism that involved the transcription factor NF-κB. Mice deficient in miR-22, but not wild-type mice, showed attenuated T H 17 responses and failed to develop emphysema after exposure to smoke or nCB. We further found that miR-22 controlled the activation of APCs and T H 17 responses through the activation of AP-1 transcription factor complexes and the histone deacetylase HDAC4. Thus, miR-22 is a critical regulator of both emphysema and T H 17 responses.

Dysregulation of Th17 and Treg cells contributes to the pathophysiology of many autoimmune diseases. Herein, we show that itaconate, an immunomodulatory metabolite, inhibits Th17 cell differentiation and promotes Treg cell differentiation by orchestrating metabolic and epigenetic reprogramming. Mechanistically, itaconate suppresses glycolysis and oxidative phosphorylation in Th17- and Treg-polarizing T cells. Following treatment with itaconate, the S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and 2-hydroxyglutarate levels are decreased by inhibiting the synthetic enzyme activities in Th17 and Treg cells, respectively. Consequently, these metabolic changes are associated with altered chromatin accessibility of essential transcription factors and key gene expression in Th17 and Treg cell differentiation, including decreased RORγt binding at the Il17a promoter. The adoptive transfer of itaconate-treated Th17-polarizing T cells ameliorates experimental autoimmune encephalomyelitis. These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases. Dysregulation of T cell homeostasis is known to contribute to the immunopathology of autoimmune diseases. Here the authors show that itaconate impacts autoimmune pathology by altering T cells via modulation of metabolic and epigenetic programs.