IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3<sup>+</sup>regulatory T cells

Korn, Thomas; Mitsdoerffer, Meike; Croxford, Andrew L.; Awasthi, Amit; Dardalhon, Valérie; Galileos, George; Vollmar, Patrick; Stritesky, Gretta L.; Kaplan, Mark H.; Waisman, Ari; Kuchroo, Vijay K.; Oukka, Mohamed

doi:10.1073/pnas.0809850105

Cited by 479 publications

(390 citation statements)

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“…Indeed, IL-10 À/À gp130 fl/fl CD4-Cre 1 mice infected with T. muris showed a significantly higher percentage of CD4 1 CD25 1 Foxp3 1 Treg at days 14 and 21 p.i., when compared with IL-10 À/À gp130 fl/fl or WT mice, indicating that gp130 signalling in T cells is important in mediating the shift from Treg to Th17 cells. Recently, Korn and colleagues demonstrated that IL-6 signalling inhibits the conversion from conventional T cells into Foxp3-expressing Treg in vivo using a model of EAE [44]. Our results corroborate this finding and provide additional evidence that the disruption of the IL-6/gp130 signalling pathway in T cells leads to a preferential activation of Treg in vivo and controls the switch between Treg and Th17 cells.…”

Section: Discussionsupporting

confidence: 88%

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

et al. 2009

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Gp130 is the common receptor of the IL-6 family of cytokines and is involved in many biological processes, including acute phase response, inflammation and immune reactions. To investigate the role of gp130 under inflammatory conditions, T-cell-specific conditional gp130 mice were first bred to the IL-10-deficient background and were then infected with the gastrointestinal nematode Trichuris muris. While IL-10 À/À mice were highly susceptible to T. muris, developed a mixed Th1/Th17 response and displayed severe inflammation of the caecum, infection of mice with an additional T-cell-specific deletion of gp130 signalling completely reversed the phenotype. These mice showed an accelerated worm expulsion that was associated with the rapid generation of a strong Th2 immune response and a significant increase in Foxp3-expressing Treg. Therefore, gp130 signalling in T cells regulates a switch between proinflammatory and pathogenic Th1/Th17 cells and regulatory Th2/Treg in vivo. Taken together, the data demonstrate that gp130 signalling in T cells is a positive regulator of inflammatory processes, favouring the Th1/Th17 axis.Key words: Cytokine receptor . Helminthic infection . Inflammation Th1/Th2/Th17 cells Transgenic mice IntroductionThe common receptor gp130 is constitutively expressed on immune and non-immune cells and is used by all members of the IL-6 family, which comprises IL-6, IL-11, leukaemia inhibitory factor, oncostatin M and the recently characterized cytokine IL-27, among others [1,2]. While gp130 acts as the obligate signalling subunit, each cytokine first binds to its specific receptor, which accounts for the difference in activities [3,4]. The lethality of mice with classical disruptions of two gp130 alleles demonstrated that gp130 signalling is important for the development of the nervous and hematopoietic systems [5,6]. Moreover, signals mediated by gp130 regulate multiple other biological functions, including acute phase response, immune reactions and inflammation [7,8]. The receptor is also involved in sustaining the disease state in inflammatory bowel disease, rheumatoid arthritis (RA) or MS [9][10][11]. The Th pathway is composed of, at least, three distinct subsets: Th1 cells produce IFN-g and are involved in the fight against intracellular pathogens. The Th2 immune response with T cells producing IL-4, IL-5 and IL-13 provides immunity to helminths [2]. Th17 cells produce cytokines like IL-17, IL-22 and mediate immunity to extracellular bacteria and fungi, but are also responsible for autoimmunity and inflammation [12,13]. Development of naïve T cells to Th17 cells requires the presence of IL-6, TGF-b1 and the transcription factor RORgt [14][15][16][17]. [20,21]. Since TGF-b1 is a common factor for Treg and Th17 cells, it is possible that a switch from Th17 to Treg exists in vivo in the absence of IL-6 signalling in T cells. The gastrointestinal helminth Trichuris muris is a good model to investigate Th-cell pathways. In common inbred mouse strains (BALB/c, C57BL/6), infection with T. muris is...

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Section: Discussionsupporting

confidence: 88%

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

et al. 2009

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“…In an EAE model, CD4 + T cells producing both IL-17 and IFNg are observed in the CNS (54)(55)(56). It is still controversial whether these IL-17/IFN-g double-producing T cells are Th1 or Th17 cells, but they do contribute to EAE pathogenesis (54).…”

Section: Discussionmentioning

confidence: 99%

Ecto-Nucleoside Triphosphate Diphosphohydrolase 7 Controls Th17 Cell Responses through Regulation of Luminal ATP in the Small Intestine

Kusu

Kayama

Kinoshita

et al. 2013

The Journal of Immunology

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Extracellular ATP is released from live cells in controlled conditions, as well as dying cells in inflammatory conditions, and, thereby, regulates T cell responses, including Th17 cell induction. The level of extracellular ATP is closely regulated by ATP hydrolyzing enzymes, such as ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases). ENTPDase1/CD39, which is expressed in immune cells, was shown to regulate immune responses by downregulating the ATP level. In this study, we analyzed the immunomodulatory function of ENTPDase7, which is preferentially expressed in epithelial cells in the small intestine. The targeted deletion of Entpd7 encoding ENTPDase7 in mice resulted in increased ATP levels in the small intestinal lumen. The number of Th17 cells was selectively increased in the small intestinal lamina propria in Entpd7−/− mice. Th17 cells were decreased by oral administration of antibiotics or the ATP antagonist in Entpd7−/− mice, indicating that commensal microbiota-dependent ATP release mediates the enhanced Th17 cell development in the small intestinal lamina propria of Entpd7−/− mice. In accordance with the increased number of small intestinal Th17 cells, Entpd7−/− mice were resistant to oral infection with Citrobacter rodentium. Entpd7−/− mice suffered from severe experimental autoimmune encephalomyelitis, which was associated with increased numbers of CD4+ T cells producing both IL-17 and IFN-γ. Taken together, these findings demonstrate that ENTPDase7 controls the luminal ATP level and, thereby, regulates Th17 cell development in the small intestine.

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“…Thus, the precise mechanisms underlying the contribution of IL-23 to Th17 cell differentiation and function in vivo remain to be elucidated. It was recently shown that mice deficient for gp130 (a shared receptor subunit for IL-6) mounted efficient Th17 responses and developed experimental autoimmune encephalomyelitis (EAE) after depletion of Treg cells, suggesting that IL-6 signaling was dispensable for the induction of pathogenic Th17 cells in vivo, at least in the absence of Treg cells [32]. These results highlight the complexity of the cytokine-induced Th17 differentiation program, suggesting that in vivo Th17 cell differentiation can be driven by multiple proinflammatory cytokines (IL-6, IL-21, IL-23 and/or other yet unidentified factors).…”

Section: Unique Cytokine Environment For Th17 Cell Differentiationmentioning

confidence: 99%

Transcriptional regulatory networks in Th17 cell differentiation

Zhou

Littman

2009

Current Opinion in Immunology

167

131

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SummaryUpon encountering antigen in the context of antigen presenting cells, naïve CD4 + T cells undergo differentiation into effector T helper (Th) cells, which can secrete high levels of cytokines and other immunomodulators to mediate host defense and tissue inflammation. During the past three years, the immunology field has witnessed an explosion of research advances in the biology of Th17 cells, the most recently described subset of T helper cells, which play critical roles in host immunity and inflammation. Here we review emerging data on transcriptional regulatory networks that govern the differentiation program of Th17 cells, and focus on how the orphan nuclear receptor RORγt coordinates this process in concert with diverse cytokine-induced transcription factors.

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IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3⁺regulatory T cells

Cited by 479 publications

References 33 publications

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

Ecto-Nucleoside Triphosphate Diphosphohydrolase 7 Controls Th17 Cell Responses through Regulation of Luminal ATP in the Small Intestine

Transcriptional regulatory networks in Th17 cell differentiation

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IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+regulatory T cells

Cited by 479 publications

References 33 publications

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

Ecto-Nucleoside Triphosphate Diphosphohydrolase 7 Controls Th17 Cell Responses through Regulation of Luminal ATP in the Small Intestine

Transcriptional regulatory networks in Th17 cell differentiation

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IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3⁺regulatory T cells