Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10

Stumhofer, Jason S.; Silver, Jonathan S.; Laurence, Arian; Porrett, Paige M.; Harris, Tajie H.; Turka, Laurence A.; Ernst, Matthias; Saris, Christiaan J. M.; O’Shea, John J.; Hunter, Christopher A.

doi:10.1038/ni1537

Cited by 710 publications

(786 citation statements)

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“…The blended phenotype of 'T H 2/T H 1' cells that co-express IL-4 and IFNγ (as well as GATA3 and T-bet) or the induction of IL-10 expression by T H 1 cells can reduce the collateral damage associated with excessive T H 1 cell responses 20,35,42,195 . Extinction of pathogenic immune responses, such as those driven by T H 17 cells, is aided by the conversion of T H 17 cells into IL-10-producing T R 1 cells 41,44,[196][197][198] .…”

Section: Beneficial T Cell Plasticitymentioning

confidence: 99%

“…TGFβ is crucial for the conversion of T H 17 cells towards a regulatory phenotype through the promotion of forkhead box P3 (FOXP3) or IL-10 expression [39][40][41] . In addition, the pleiotropic cytokine IL-27 can induce IL-10 expression by various inflammatory subsets to promote regulatory functions, as well as induce the generation of type 1 regulatory T (T R 1) cells de novo [42][43][44] . Conversely, the treatment of tT Reg cells from mice or humans with the T H 17 cellinducing cytokines IL-6, IL-1β and IL-23 (especially in combination) can destabilize FOXP3 expression and induce IL-17 production in vitro 17,18 , and STAT3 (which is activated in response to these cytokines) is required for reprogramming 45 .…”

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confidence: 99%

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Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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Section: Beneficial T Cell Plasticitymentioning

confidence: 99%

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confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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“…Recent studies have demonstrated that IL-27 suppresses IL-17 production by naïve T cells stimulated with IL-6 and TGF-b in combination with anti-CD3 and anti-CD28 [58]. It has been reported that IL-27 and IL-6 can induce IL-10 production from Th1, Th2 and Th17 cells through activation of STAT-1 and STAT-6 [109]. Furthermore, it has been demonstrated that IL-27 inhibits IL-17 production and EAE by inducing IL-10 from IFN-g 1 T-bet 1 Foxp3 À T cells [110].…”

Section: Regulation Of Il-17-secreting T Cellsmentioning

confidence: 99%

Induction, function and regulation of IL‐17‐producing T cells

2008

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Recent reports have provided convincing evidence that IL-17-producing T cells play a key role in the pathogenesis of organ-specific autoimmune diseases, a function previously attributed exclusively to IFN-c-secreting Th1 cells. Furthermore, it appears that IL-17-producing T cells can also function with Th1 cells to mediate protective immunity to pathogens. Although much of the focus has been on IL-17-secreting CD4 1 T cells, termed The main function of IL-17-secreting T cells is to mediate inflammation, by stimulating production of inflammatory cytokines, such as TNF-a, IL-1b and IL-6, and inflammatory chemokines that promote the recruitment of neutrophils and macrophages.Key words: Autoimmunity . IL-17 . Infection . Inflammation IntroductionMore than 20 years ago Mosmann and Coffman reported that distinct CD4 1 T-cell subtypes, termed Th1 and Th2 cells, could be distinguished on the basis of cytokine secretion and function [1]. The Th1-Th2 model provided a useful but simplistic basis for our understanding of the mechanisms of immunity to infection and also attempted to explain the role of T cells in the pathogenesis of autoimmunity and allergy/asthma. The original hypothesis was that IFN-g-secreting CD4 1 cells mediated protective immunity to intracellular pathogens by promoting macrophage activation and stimulating production of complement fixing and virus neutralizing antibodies, but also promoted inflammatory responses and mediated the pathology in certain autoimmune diseases. In contrast, CD4 1 T cells that secreted IL-4, IL-5, IL-10 and IL-13 were considered to be the main helper T cells providing help for B-cell production of antibody, especially IgG1 in mice, and mediated protective immunity to extracellular pathogens. These Th2 cells were also anti-inflammatory, controlling Th1 responses, but at the same time mediated allergic reactions and had an inflammatory and pathological role in asthma.The identification of additional T-cell subtypes has led to a shift in the Th1-Th2 paradigm and has helped to explain some anomalies in the original model. In the mid 1990s suppressor T cells were re-discovered as Treg cells and were shown to have a major role in controlling immune responses to self-antigens, thereby preventing autoimmunity. Furthermore, these cells rather than the reciprocal Th1 or Th2 populations were shown to be the major regulator of effector T cells, functioning to maintain self-tolerance, prevent autoimmunity and limit collateral damage during immune responses to pathogens [2,3].There were a number of other observations which could not be explained on the basis of the two Th1 and Th2 subtypes. Mini-ReviewDespite the assumption that Th1 cells mediated autoimmunity, mice deficient in IFN-g or IFN-g receptors were found to have increased susceptibility to EAE and collagen-induced arthritis (CIA) [4,5]. Furthermore, EAE was exacerbated in mice deficient in the Th1 polarizing cytokine, 7]. It was then discovered that mice deficient in the novel IL-12 family member, IL-23 were resistant to EAE [6]....

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“…IL-27 also promotes the production of IL-10 by various effector CD4 + T cell populations, including Th1 and Th2 cells and CD4 + T cells polarized under Th17-inducing conditions (20)(21)(22)(23)(24)(25). In line with these disparate roles, IL-27 signaling is essential for the generation of early protective T cell responses during Leishmania major (9) and bacillus Calmette-Guérin (8) infections but is required for the suppression of Th1-and Th17-mediated inflammation during Toxoplasma gondii, Trypanosoma cruzi, Mycobacterium tuberculosis, Leishmania donovani, and nonhealing L. major infections (17,(26)(27)(28)(29)(30)(31).…”

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confidence: 99%

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Findlay

Greig

Stumhofer

et al. 2010

The Journal of Immunology

106

123

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Successful resolution of malaria infection requires induction of proinflammatory immune responses that facilitate parasite clearance; however, failure to regulate this inflammation leads to immune-mediated pathology. The pathways that maintain this immunological balance during malaria infection remain poorly defined. In this study, we demonstrate that IL-27R–deficient (WSX-1−/−) mice are highly susceptible to Plasmodium berghei NK65 infection, developing exacerbated Th1-mediated immune responses, which, despite highly efficient parasite clearance, lead directly to severe liver pathology. Depletion of CD4+ T cells—but not CD8+ T cells—prevented liver pathology in infected WSX-1−/− mice. Although WSX-1 signaling was required for optimal IL-10 production by CD4+ T cells, administration of rIL-10 failed to ameliorate liver damage in WSX-1−/− mice, indicating that additional, IL-10–independent, protective pathways are modulated by IL-27R signaling during malaria infection. These data are the first to demonstrate the essential role of IL-27R signaling in regulating effector T cell function during malaria infection and reveal a novel pathway that might be amenable to manipulation by drugs or vaccines.

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Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10

Cited by 710 publications

References 58 publications

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Induction, function and regulation of IL‐17‐producing T cells

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

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