The contribution of transcription factor IRF1 to the interferon-γ–interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells

Kano, Shin-ichi; Sato, Kojiro; Morishita, Yasuyuki; Vollstedt, Sabine; Kim, Sun-Hwa; Bishop, Keith; Honda, Kenya; Kubo, Masato; Taniguchi, Tadatsugu

doi:10.1038/ni1538

Cited by 137 publications

(108 citation statements)

References 49 publications

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“…For instance, OX40 engagement inhibits IL-10 production along Th2 differentiation [42] and during anti-viral immune responses [43]. Moreover, we show here that OX40 signal may regulate IL-10 secretion through the modulation of IRF1, a Th1-related transcription factor [44]. We found IRF1 expressed in tumor-infiltrating but not peripheral Treg cells producing or not IL-10, respectively.…”

Section: Discussionmentioning

confidence: 55%

“…However, we could not detect any Foxp3 downregulation in tumor-infiltrating compared with peripheral Treg cells, or in IL-10-producing versus IL-10-negative Treg cells. IRF1 is a transcription factor playing essential roles in Th1 differentiation, inducing IL-12Rb1 in CD4 1 T cells [44]. Germane is the expression of IL-12Rb1 in lamina propria Treg cells [45].…”

Section: Discussionmentioning

confidence: 99%

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Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

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Treg cells maintain the tumor microenvironment in an immunosuppressive state preventing an effective anti-tumor immune response. A possible strategy to overcome Treg-cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while being induced in activated effector T cells. OX40 stimulation, by the agonist mAb OX86, inhibits Treg-cell suppression and boosts effector T-cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, the most abundant CD4 1 populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor interferon regulatory factor 1 (IRF1). Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to DCs. The CD40L/CD40 axis was required for Tem-cellmediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg-cell suppression and enhancement of the Tem-cell adjuvant effect both concurred to free DCs from immunosuppression and activate the immune response against the tumor. 3615The tumor microenvironment is characterized by an immunosuppressive cytokine milieu, which promotes immune tolerance and tumor growth. Treg cells secrete interleukin 10 (IL-10), which plays a critical role in suppressing immune responses and in particular the maturation of fully competent DCs [13][14][15]. Among tumor-infiltrating Teff cells, the subpopulation of effector memory T (Tem) cells is the most abundant. Tem cells are CD4 1 CD44 high CD62L low lymphocytes excluded from resting lymph nodes and mainly localized in peripheral tissues; upon stimulation they rapidly activate and secrete effector cytokines like IFN-g, but they have limited proliferative capacity [16]. In experimental models of immune activation, Tem cells constitutively express CD40L at levels sufficient to induce DC activation in an antigen-independent manner [17]. The CD40/CD40L axis is crucial for DC maturation and the subsequent T-cell priming. However in the tumor microenvironment this costimulatory pathway is often dampened, thus impairing the generation of an efficient anti-tumor immune response [18,19].In this study we have investigated the mechanisms by which OX86 modulates Treg-and Teff-cell functions and their reciprocal interactions with DCs at the tumor site. We propose a model of the tumor microenvironment in which, after OX86 treatment, DCs receive a lower IL-10-mediated inhibition by Treg cells on the one hand, and a stronger stimulation from Tem cells, via the CD40/CD40L axis, on the other. In this favorable condition, DCs acquire a stronger migratory ability toward the draining LNs (dLNs), thus inducing a specific anti-tumor immune response. ResultsIntratumoral ...

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

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“…The signalling pathways that promote innate cytokines that drive induction or expansion of Th17 cell have also received some attention [72]. Although a great deal is known about TLR-induced signalling in macrophages or DC that mediate IL-1, TNF-a and IL-12 production, less is known about the pathways that promote IL-23 production, except that they appear to be distinct from those that mediated IL-12-driven Th1 responses [73]. We have preliminary evidence that distinct signalling pathways are involved in TLR/NLR agonist-induced IL-23 and IL-12p70 production by murine DC (Brereton and Mills, unpublished data).…”

Section: T-cell Subtypes That Secrete Il-17mentioning

confidence: 99%

“…We have preliminary evidence that distinct signalling pathways are involved in TLR/NLR agonist-induced IL-23 and IL-12p70 production by murine DC (Brereton and Mills, unpublished data). It has been reported that MyD88-mediated activation of NF-kB, IRF-1, IRF-5 and IRF-8 plays important roles in the expression of IL-12p35 and IL-12p40 genes and in driving Th1 in responses, whereas NF-kB, IRF3, IRF5 may be involved in IL-23 and IL-17 production [72,73]. In addition, it has been demonstrated that signalling through the C-type lectin dectin-1 in DC for IL-6, TNF-a and IL-23 production and consequent Th17 development involves Syk and CARD9 [65].…”

Section: Intracellular Signalling Molecules and Transcription Factorsmentioning

confidence: 99%

“…Targeting intracellular signalling molecules or transcriptional factors involved in the activation of IL-17 or IL-23 production is an alternative approach amenable to the development of low molecular weight drugs, but is also complicated by the fact that many of the signalling pathways may not be unique to the IL-23-IL-17 axis and may also inhibit responses of other cell types involved in protective immunity. However, there is evidence that IL-12-driven Th1 responses and the IL-23-IL-17 axis may involve distinct signalling pathways in DC [73] (Brereton and Mills, unpublished data). Therefore, it may be possible to specifically block IL-23 and IL-17 production, without affecting IL-12 and Th1 responses, thus limiting the immunosuppressive effects of the immunotherapy to attenuation of pathogenic Th17 cells.…”

Section: Conclusion and Prospects For Therapies That Target Th17 Cellsmentioning

confidence: 99%

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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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T Lymphocytes: Helpers

Kawachi¹,

Kondo²

2009

Encyclopedia of Life Sciences

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Helper T lymphocytes are major histocompatibility complex (MHC) class II restricted CD4+ T cells which can be divided into several subsets of cytokine releasing patterns: T‐helper 1 (T H 1), T‐helper 2 (T H 2), T‐helper 17 (T H ‐17) and T‐follicular helper (T FH ). Following are several transcription factors especially expressed, or function differently, in each of the clonal progeny to define separable effector T‐helper cell lineages. Helper T cells orchestrate antibody production and cellular immune responses. T H 1 cells activate infected macrophages for the destruction of intracellular pathogens. T H 2 and T FH cells provide help to B cells for antibody production, which is a response aimed mainly at extracellular pathogens. T H ‐17 cells enhance neutrophil response for extracellular pathogens. Each T H subset plays a distinct role in host defence and autoimmunity. Key concepts Helper T lymphocytes are MHC class II restricted CD4+ T cells which can be divided into several subsets of cytokine releasing patterns: T‐helper 1 (T H 1), T‐helper 2 (T H 2), T‐helper 17 (T H ‐17) and T‐follicular helper (T FH ). IFNγ, IL‐4 and IL‐17 are the representative cytokines of T H 1, T H 2 and T H ‐17 cells, respectively, and are often used as subtype markers. T H 1 cells play an important role in cellular immune functions such as delayed‐type hypersensitivity or in the defence against intracellular organisms. T H 2 cells enhance antibody production from B cells. T H ‐17 cells are potent inducers of tissue inflammation in autoimmune diseases and confer protection against extracellular bacterial and fungal pathogens. T FH cells regulate the step‐wise development of antigen‐specific B‐cell immunity in B‐cell follicles of lymphoid tissues.

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The contribution of transcription factor IRF1 to the interferon-γ–interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells

Cited by 137 publications

References 49 publications

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

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

T Lymphocytes: Helpers

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