T-bet is essential for encephalitogenicity of both Th1 and Th17 cells

Yang, Yuhong; Weiner, Jeffrey L.; Liu, Yue; Smith, Anne M.; Huss, David; Winger, Ryan C.; Peng, Haiyan; Cravens, Petra D.; Racke, Michael K.; Lovett-Racke, Amy E.

doi:10.1084/jem.20082584

Cited by 255 publications

(282 citation statements)

References 60 publications

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“…As measured by other studies [16,22,23], a remarkable proportion of Th17 cells also shares the ability to produce IFN-γ. These cells, producing both IL-17 and IFN-γ, are usually named Th17/Th1.…”

Section: Discussionsupporting

confidence: 62%

Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

et al. 2011

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This study was designed to investigate the functional heterogeneity of human Th17 and how their plasticity shapes the nature of immune cell responses to inflammation and autoimmune diseases, such as systemic lupus erythematosus (SLE). We evaluated functional Th17 cell subsets based on the profile of cytokine production in peripheral blood (PB), bone marrow aspirates (BM) and lymph node biopsies (LN) from healthy individuals (n=35) and PB from SLE patients (n=34). Data were analysed by an automated method for merging and calculation of flow cytometric data, allowing us to identify eight Th17 subpopulations. Normal BM presented lower frequencies of Th17 (p=0.006 and p=0.05) and lower amount of IL-17 per cell (p=0.03 and p=0.02), compared to normal PB and LN biopsies. In the latter tissues were found increased proportions of Th17 producing TNF-α or TNF-α/IL-2 or IFN-γ/TNF-α/IL-2, while in BM, Th17 producing other cytokines than IL-17 was clearly decreased. In SLE patients, the frequency of Th17 was higher than in control, but the levels of IL-17 per cell were significantly reduced (p<0.05). Among the eight generated subpopulations, despite the great functional heterogeneity of Th17 in SLE, a significant low proportion of Th17 producing TNF-α was found in inactive SLE, while active SLE showed a high proportion producing only IL-17. Our findings support the idea that the functional heterogeneity of Th17 cells could depend on the cytokine microenvironment, which is distinct in normal BM as well as in active SLE, probably due to a Th1/Th2 imbalance previously reported by our group.

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Section: Discussionsupporting

confidence: 62%

Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

et al. 2011

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“…However, in the case of encephalitogenic T cells, we and others have found that myelin-specific Th17 cells differentiated with IL-6 and TGFb are not encephalitogenic (Yang et al, 2009;Ghoreschi et al, 2010;Lee et al, 2015). In fact, TGFb is a negative regulator of T-bet, a key transcription factor in encephalitogenic T cells, irrespective of whether it has a Th1 or Th17 phenotype (Gocke et al, 2007;Yang et al, 2009;Lee et al, 2015). Thus, suppression of the TGFb pathway enhances T-bet expression, as well as promotes the differentiation of pathogenic Th17 cells, suggesting that miRNAs that suppress TGFb signalling may promote the development of autoreactive effector T cells.…”

Section: Discussionmentioning

confidence: 54%

“…TGFb has been shown to promote the development of Th17 cells in the presence of IL-6 in mice (Bettelli et al, 2006;Mangan et al, 2006;Veldhoen et al, 2006), suggesting that diminished TGFb signalling may negatively modulate Th17 cells. However, in the case of encephalitogenic T cells, we and others have found that myelin-specific Th17 cells differentiated with IL-6 and TGFb are not encephalitogenic (Yang et al, 2009;Ghoreschi et al, 2010;Lee et al, 2015). In fact, TGFb is a negative regulator of T-bet, a key transcription factor in encephalitogenic T cells, irrespective of whether it has a Th1 or Th17 phenotype (Gocke et al, 2007;Yang et al, 2009;Lee et al, 2015).…”

Section: Discussionmentioning

confidence: 70%

MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

Severin

Lee

Liu

et al. 2016

Brain

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“…Neither overexpression of IL-17A in T cells nor its complete loss had an Correspondence: Dr. Lawrence Steinman e-mail: steinman@stanford.edu impact on clinical EAE [9]. More recently it has been shown that T-bet is more critical than IL-17 itself in the development of clinical EAE [10]. Thus, even though experiments in EAE were pivotal in defining the Th17 pathway, it is ironic that the role of IL-17 in EAE is highly controversial, (see Table 1.…”

Section: See Accompanying Article By Chen Et Almentioning

confidence: 99%

Shifting therapeutic attention in MS to osteopontin, type 1 and type 2 IFN

Steinman

2009

Eur J Immunol

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It is widely debated whether MS is mediated solely by Th1, or solely by Th17, whether it might be mediated by both pathways, or perhaps by neither pathway. We must integrate the following four facts: first, MS lesions have a signature of IL-6-, IL-17-, osteopontin-and IFN-driven transcriptional activity. Second, MS is worsened with administration of IFN-c, the quintessential type 2 IFN and Th1 cytokine. Third, blockade of TNF-a worsened MS in clinical trials. Fourth, inhibiting the main driver of Th17, IL-23, failed to modulate relapsing-remitting MS (RRMS). Against this backdrop, standing outside the framework of the Th1 and Th17 pathways are the type 1 IFN, notably IFN-b, the most widely used approved therapy for RRMS. A paper in this issue of the European Journal of Immunology demonstrates that IFN-b suppresses production in CD4 1 T cells of both osteopontin and IL-17. In this commentary, the roles of these two molecules, i.e. osteopontin and IL-17, are discussed in relation to the pathogenesis of MS. Osteopontin may be more important than Th1 or Th17 in the pathogenesis of RRMS. Trials targeting this small integrin-binding protein ought to be pursued in RRMS. The notion that Th1 is the main driver of autoimmune tissue damage has largely been replaced by the notion that Th17 is critical for autoimmune-mediated tissue damage [5]. The central importance of IL-23, the key cytokine for Th17 development, has contributed greatly to the general enthusiasm for the notion that Th17 and in particular IL-17 is the key mediator of tissue damage in autoimmune disease [6].As a matter of fact there are actually three forms of EAE, one driven by Th1 [7], another by Th17 [7] and surprisingly a third type driven by Th2 that might be best called experimental allergic encephalomyelitis, as the disease was called in the 1940s through about 1980 [5,8]. Somehow EAE is now considered experimental autoimmune encephalomyelitis. Thus, tissue damage in EAE can be the result of any one of the three major lineages [5]. This is not widely appreciated when we read that Th17 is the major mediator of tissue damage in so many papers presently. Th17 is not the major mediator; it is merely one of the major mediators of tissue damage in EAE.The role of IL-17 itself is ever more controversial. Neither overexpression of IL-17A in T cells nor its complete loss had an Table 1.)Even with these clarifications from the EAE model, the facts in MS do not support, thus far, a major role for Th17 in relapsingremitting MS (RRMS). MS lesions have a signature of IL-6-, IL-17-, osteopontin-and IFN-driven transcriptional activity [11,12]. What do we know about these molecules in MS? IL-23 is the main driver of Th17 in man [13]. Despite widespread success in ameliorating EAE with various means of blocking IL-23, a clinical trial in MS with anti-IL-12p40 failed to show any effect in RRMS [14]. This raises a major question mark about the importance of Th17 in MS. Of course, IL-12p40 modulates both Th1 and Th17 [13]. The importance of Th1 in MS is widely recognized...

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T-bet is essential for encephalitogenicity of both Th1 and Th17 cells

Cited by 255 publications

References 60 publications

Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

Shifting therapeutic attention in MS to osteopontin, type 1 and type 2 IFN

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