T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17

Rangachari, Manu; Mauermann, Nora; Marty, René R.; Dirnhofer, Stephan; Kurrer, Michael; Komnenovic, Vukoslav; Penninger, Josef; Eriksson, Urs

doi:10.1084/jem.20052222

Cited by 243 publications

(256 citation statements)

References 64 publications

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“…This is in accordance with a recent study in which both T-bet ϩ/ϩ and T-bet Ϫ/Ϫ pathogenic CD4 ϩ T cell lines produced elevated levels of IFN-␥ or IL-4, respectively, but also secreted significant and comparable amounts of IL-17 (26). Interestingly, one model of autoimmunity, experimental autoimmune myocarditis (EAM), has been found to have increased disease severity in T-bet-deficient mice (26). Increased numbers of Th17 cells and decreased numbers of IFN-␥ ϩ CD8 ϩ T cells in the hearts of T-bet-deficient mice led the authors to conclude that T-bet is a negative regulator of EAM.…”

Section: Discussionsupporting

confidence: 93%

“…However, we found Th17 cells differentiated in the CNS of EAE-affected mice in the presence of IFN-␥-producing Th1 cells. This is in accordance with a recent study in which both T-bet ϩ/ϩ and T-bet Ϫ/Ϫ pathogenic CD4 ϩ T cell lines produced elevated levels of IFN-␥ or IL-4, respectively, but also secreted significant and comparable amounts of IL-17 (26). Interestingly, one model of autoimmunity, experimental autoimmune myocarditis (EAM), has been found to have increased disease severity in T-bet-deficient mice (26).…”

Section: Discussionsupporting

confidence: 90%

“…Results shown are representative of two independent experiments. in vivo (26,31). It has also been speculated that IFN-␥-deficient mice develop severe EAE because of an enhanced myelin-specific Th17 cell population (17,24).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

Gocke¹,

Cravens²,

Ben³

et al. 2007

The Journal of Immunology

236

224

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IL-17-producing T cells (Th17) have recently been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. However, little is known about the transcription factors that regulate these cells. Although it is clear that the transcription factor T-bet plays an essential role in the differentiation of IFN-γ-producing CD4+ Th1 lymphocytes, the potential role of T-bet in the differentiation of Th17 cells is not completely understood. In this study, therapeutic administration of a small interfering RNA specific for T-bet significantly improved the clinical course of established EAE. The improved clinical course was associated with suppression of newly differentiated T cells that express IL-17 in the CNS as well as suppression of myelin basic protein-specific Th1 autoreactive T cells. Moreover, T-bet was found to directly regulate transcription of the IL-23R, and, in doing so, influenced the fate of Th17 cells, which depend on optimal IL-23 production for survival. We now show for the first time that suppression of T-bet ameliorates EAE by limiting the differentiation of autoreactive Th1 cells, as well as inhibiting pathogenic Th17 cells via regulation of IL-23R.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 90%

See 1 more Smart Citation

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

Gocke¹,

Cravens²,

Ben³

et al. 2007

The Journal of Immunology

236

224

View full text Add to dashboard Cite

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“…IL-17 production was also shown to be enhanced in IFN-g À/À mice infected with BCG, whereas addition of recombinant IFN-g inhibited in vitro activation of Th17 cells by DC infected with BCG [100]. In an experimental autoimmune myocarditis model, T-bet-mediated IFN-g production by CD8 1 T cells was found to regulate IL-17 production and thereby control the severity of myocarditis [101]. IFN-g may also play a role in controlling pathogenic T cells in autoimmunity by inducing peripheral conversion of CD4 1 CD25 À T cells into CD4 1 FoxP3 1 Treg cells [102].…”

Section: Regulation Of Il-17-secreting T Cellsmentioning

confidence: 94%

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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“…Huber and others discovered that male mice who mostly had a Th1 cell-mediated immune response were more susceptible to the CVB3 virus than female mice who had a Th2-mediated immune response [3]. Rangachari et al reported that Th17 cells and its cytokine, IL-17, increased the severity of viral myocarditis and autoimmune myocarditis [4]. Treg cells could inhibit the expression of inflammatory cytokines and attenuate the severity of viral myocarditis [5].…”

Section: Introductionmentioning

confidence: 99%

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4⁺ T cell differentiation

et al. 2018

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Many studies have found that abnormalities in the proportion and differentiation of CD4+ T cells (Th cells) are closely related to the pathogenesis of viral myocarditis (VMC). Our previous research indicates that the cholinergic anti-inflammatory pathway (CAP) attenuates the inflammatory response of VMC and downregulates the expression of cytokines in Th1 and Th17 cells. This suggests that the cholinergic anti-inflammatory pathway likely attenuates the inflammatory response in VMC by altering Th cell differentiation. The aim of this study is to investigate the effect of CAP on CD4+ T cell differentiation in VMC mice. CD4+ T cells in the spleen of VMC mice were obtained and cultured in the presence of nicotine or methyllycaconitine (MLA). Cells were harvested and analyzed for the percentage of each Th cell subset by flow cytometry and transcription factor release by Western blot. Then, we detected the effect of CAP on the differentiation of Th cells in vivo. Nicotine or MLA was used to activate and block CAP, respectively, in acute virus-induced myocarditis. Nicotine treatment increased the proportion of Th2 and Treg cells, decreased the proportion of Th1 and Th17 cells in the spleen, reduced the level of proinflammatory cytokines, and attenuated the severity of myocardium lesions and cellular infiltration in viral myocarditis. MLA administration had the opposite effect. Our result demonstrated that CAP effectively protects the myocardium from virus infection, which may be attributable to the regulation of Th cell differentiation.

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T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17

Cited by 243 publications

References 64 publications

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

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

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4⁺ T cell differentiation

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T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17

Cited by 243 publications

References 64 publications

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

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

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4+ T cell differentiation

Contact Info

Product

Resources

About

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4⁺ T cell differentiation