The inhibitory cytokine IL-35 contributes to regulatory T-cell function

Collison, Lauren W.; Workman, Creg J.; Kuo, Timothy; Boyd, Kelli L.; Wang, Yao; Vignali, Kate M.; Cross, Rebecca; Sehy, David; Blumberg, Richard S.; Vignali, Dario A.A.

doi:10.1038/nature06306

Cited by 1,719 publications

(1,641 citation statements)

References 42 publications

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“…Treg can interact with other immune populations via soluble factors and/or via cell-contactdependent mechanisms. Whereas in vivo studies have suggested a major role for soluble factors, such as IL-10 [41], TGF-b [42], or IL-35 [43], most in vitro experiments described a cell-contactdependent mechanism, involving CTLA-4 [44,45], GITR [46], Perforin [33], or Granzyme B [34]. Our data suggest that Perforin/ Granzyme-induced apoptosis does not play a major role in Tregmediated suppression of mouse gd-T-cell activity.…”

Section: Discussionmentioning

confidence: 51%

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

et al. 2009

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cd T cells are highly cytolytic lymphocytes that produce large amounts of pro-inflammatory cytokines during immune responses to multiple pathogens. Furthermore, their ability to kill tumor cells has fueled the development of cd-T-cell-based cancer therapies. Thus, the regulation of cd-T-cell activity is of great biological and clinical relevance. Here, we show that murine CD4 1 CD25 1 ab T cells, the vast majority of which express the Treg marker, Foxp3, abolish key effector functions of cd T cells, namely the production of the pro-inflammatory cytokines, IFN-c and IL-17, cytotoxicity, and lymphocyte proliferation in vitro and in vivo. We further show that suppression is dependent on cellular contact between Treg and cd T cells, results in the induction of an anergic state in cd lymphocytes, and can be partially reversed by manipulating glucocorticoid-induced TNF receptor-related protein (GITR) signals. Our data collectively dissect a novel mechanism by which the expansion and pro-inflammatory functions of cd T cells are regulated. IntroductionThe integration of multiple effector and regulatory mechanisms dictates the course of immune responses to self and non-self antigens. gd T cells are innate-like lymphocytes known to mount robust responses to infectious pathogens [1] and tumors [2], while also regulating tissue homeostasis and repair [3]. Importantly, several of these functions are non-redundant, as demonstrated by the immunopathology phenotypes of TCR-d-deficient mice [4]. It is also well documented that upon pathogen challenge (for example, with Plasmodium falciparum, Mycobacterium tuberculosis, Haemophilus influenzae, or Streptococcus pneumoniae), gd T cells are one of the immune populations that expands most dramatically in human peripheral blood [1,5,6].In contrast with adaptive ab T cells, activated gd lymphocytes are capable of ''immediate'' cytotoxicity and cytokine secretion [5]. In fact, we have recently shown that murine gd T cells become functionally competent in the thymus, particularly regarding the production of pro-inflammatory cytokines . Furthermore, several reports have demonstrated the crucial contributions of gd T cells to the reservoirs of such cytokines in the context of anti-tumor immunity [8], immune responses to infection [9], and autoimmunity [9,10]. While these data highlight the importance of understanding how the [17], and monocytes/macrophages [18]. As a result, CD4 1 CD25 1 ab T cells, and particularly those that develop in the thymus through a Foxp3-dependent genetic program [19,20], so-called ''naturally occurring '' Treg (nTreg), are pivotal to maintaining immune homeostasis and preventing inflammatory and autoimmune diseases [21]. On the other hand, Treg-suppressive functions are also known to diminish immunity to pathogens and to tumors [22,23]. Provocatively, an inverse correlation between circulating human Treg frequencies and gd-T-cell numbers in cancer patients has been recently reported [24].Building on these foundations, we show here that Treg suppress gd-T-cell ...

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Section: Discussionmentioning

confidence: 51%

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

et al. 2009

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“…157 IL-35 was initially described as a Treg-specific cytokine with potent immunosuppressive properties. 158 Studies conducted with IL-35-overexpressing cancer cells reported a role for IL-35 in promoting tumor growth through the suppression of T-cell responses. 159 rejection of breast cancer TSA-IL-12 cells was dependent on CD8 cytotoxic T cells, secreting IFN-g. 43 However, tumor rejection in IL-12-transduced C26 colon carcinoma was partially dependent on GM-CSF-producing CD4 T cells or NK cells, but independent of IFN-g. 46 IL-12-responsive T cells were also ascribed a major role in rejection of tumors of the central nervous system.…”

Section: Mechanisms Of Tumor Protection Through Il-12mentioning

confidence: 99%

New insights into IL-12-mediated tumor suppression

et al. 2014

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During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

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Section: Regulation Of Il-17-secreting T Cellsmentioning

confidence: 99%

“…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]. Finally, it has recently been reported that IL-35, a heterodimer of Epstein-Barr-virus-induced gene 3 and IL-12p35, which is highly expressed by mouse Foxp3 1 Treg cells [111] and induces IL-10 production by Treg cells, suppresses Th17 cell differentiation and attenuates CIA [112].The role of TGF-b in regulating IL-17 production by T cells is more controversial. Although TGF-b is secreted by antigenspecific Treg cells, in particular Th3 cells in the gut, and induces peripheral conversion of CD4 1 CD25 À Foxp3 À T cells to CD4 1 CD25 1 Foxp3 1 Treg cells [113], this cytokine has also been shown to function with IL-6 or IL-21 to promote the differentiation of murine and human Th17 cells from naïve CD4 1 T cells in vitro [39][40][41][43][44][45].…”

mentioning

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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The inhibitory cytokine IL-35 contributes to regulatory T-cell function

Cited by 1,719 publications

References 42 publications

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

New insights into IL-12-mediated tumor suppression

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

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