Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis

Fuss, Ivan J.; Heller, Frank; Boirivant, Monica; León, Francisco; Yoshida, Masaru; Fichtner‐Feigl, Stefan; Yang, Zhaopeng; Exley, Mark A.; Kitani, Atsushi; Blumberg, Richard S.; Mannon, Peter J.; Strober, Warren

doi:10.1172/jci200419836

Cited by 216 publications

(248 citation statements)

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“…On the other hand, in UC the inflammatory response seems to be dominated by Th2 lymphocytes, which secrete high amounts of IL-5 and IL-13 (Fuss et al 2004). The increase in circulating IL-10 level in UC demonstrated in this study, in turn, seems to result from the activity of T Reg cells.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory cytokines and IL-10 in inflammatory bowel disease and colorectal cancer patients

Szkaradkiewicz

Marciniak

Chudzicka-Strugała

et al. 2009

Arch. Immunol. Ther. Exp.

114

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Introduction: The aim of the study was to describe the levels of circulating monocyte/macrophage pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8) and an anti-inflammatory cytokine (IL-10) in inflammatory bowel disease (IBD) and colorectal cancer (CRC) patients and healthy controls. Materials and Methods:The study was conducted on 15 healthy individuals, 20 patients with ulcerative colitis (UC), 12 with Crohn's disease (CD), and 15 with CRC (Dukes' stage B). Blood serum cytokine levels were measured by ELISA. Results: The patients with UC had significantly higher levels of the pro-inflammatory cytokines and of circulating IL-10 than the healthy controls. The patients with CD and CRC had the same specific pattern of serum cytokines of significantly elevated levels of the pro-inflammatory cytokines, but the IL-10 levels were within the range found in the healthy individuals. Conclusions: Thus our results demonstrate that both IBD and CRC are linked with an intensified production of a wide array of monocyte/macrophage pro-inflammatory cytokines which is not accompanied by elevated levels of circulating IL-10, except for its insufficiently inhibitory elevation in UC patients.

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Section: Discussionmentioning

confidence: 99%

Proinflammatory cytokines and IL-10 in inflammatory bowel disease and colorectal cancer patients

Szkaradkiewicz

Marciniak

Chudzicka-Strugała

et al. 2009

Arch. Immunol. Ther. Exp.

114

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“…Although IL-13 is mainly produced by T cells [39,40], several sources of IL-13 have been suggested, including human and mouse NK cells [16,17], NKT cells [41], basophils [25,26] and mast cells [42]. To specifically address the question of which cell populations produce IL-13 during this IL-4/B7-independent in vivo immune response to T. muris, we performed cell sorting and quantitative RT-PCR.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous findings support this concept and further suggest that IL-13 can mediate resistance to T. muris in the absence of both IL-4 signaling and B7 costimulation [8]. These studies indicated either a novel B7-independent pathway of CD4 + T cell differentiation leading to IL-13 but not IL-4 expression or an alternative cell source that can differentiate to produce IL-13 if B7 is blocked and/or IL-4 is neutralized.Although IL-13 is mainly produced by T cells [39,40], several sources of IL-13 have been suggested, including human and mouse NK cells [16,17], NKT cells [41], basophils [25,26] and mast cells [42]. To specifically address the question of which cell populations produce IL-13 during this IL-4/B7-independent in vivo immune response to T. muris, we performed cell sorting and quantitative RT-PCR.…”

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confidence: 99%

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Liu

Whitmire

et al. 2006

Eur J Immunol

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IL-4 and IL-13 are up-regulated during in vivo responses to many nematode parasites, but increasing evidence suggests that increases in IL-13 can also occur independently of the IL-4-dominant Th2 response. Blocking B7 after Trichuris muris inoculation inhibits resistance and IL-4 elevations, instead resulting in an IFN-c-dominant response associated with susceptibility. However, blocking IFN-c under these conditions restores IL-13-dependent resistance. In this study, we examined the mechanism of IL-13 upregulation and associated protection during this in vivo immune response. CD4 + T cells and DX5 + TCR -cells were identified as the major producers of IL-13, and the DX5 + TCRcells were phenotyped as NK cells, since they expressed CD11b, IL-2Rb and Ly49C but not c-kit or FceRI. NK cell-derived IL-13 elevations were T cell-dependent, as CD4 + T cell depletion blocked IL-13 production by mesenteric lymph node cells and induced susceptibility. IL-13 expression was increased independently of IL-12; however, blocking IL-18 function inhibited IL-13 production and increased susceptibility. These results indicate that CD4 + T cells and NK cells are the major sources of IL-13 during the in vivo Th1 response induced by B7 blockade and that under these conditions, IL-18 is specifically required for the in vivo up-regulation of IL-13 production and associated host protection. IntroductionThe host protective response that develops following infection varies greatly with the particular pathogen. The type 2 immune response, associated with high levels of IL-4, IL-13 and other Th2 cytokines, provides protection against intestinal nematode parasites [1-3], while type 1 immunity, associated with an IFNc-dominant response, mediates resistance against many viruses and bacteria [4,5]. The events that lead to the development of type 1 and type 2 immunity are generally thought to be distinct, and as each response matures, production of characteristic cytokines can down-regulate the reciprocal response, resulting in further polarization.Typically, type 2 responses leading to resistance require the development of IL-4-producing effector CD4 + T cells, which then utilize autocrine IL-4 for their rapid expansion [3]. These Th2 cells mediate worm expulsion through their production of Th2 cytokines, with IL-4 and IL-13 being particularly important for the expulsion of gastrointestinal nematode parasites [1,2]. The development and expansion of IL-4-producing T cells is preferentially dependent on B7 costimulatory molecules [6,7], and in a number of infectious diseases, B7 blockade can actually deviate a Th2 response to an IFN-c-dominant Th1 response [8,9]. In the Th2 cell differentiation model just described, blockade of IL-4 production with B7 antagonists would be expected to also inhibit IL-13 production. However, other studies suggest that under certain circumstances IL-4 and IL-13 are regulated independently, and certain signaling pathways involving c-maf [10] and can differentially regulate these two cytokines. Consistent with these fin...

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“…Important progress has also been made concerning the functions of non-iNKT cells. A role for non-iNKT cells has been documented in some inflammatory/autoimmune diseases (hepatitis, experimental autoimmune encephalomyelitis, ulcerative colitis), infectious diseases (Trypanosoma cruzi) and in tumour immunity (Ambrosino et al, 2007;Duthie et al, 2005;Fuss et al, 2004;Halder et al, 2007). Interestingly, iNKT and non-iNKT cells exert opposite and counteractive roles in the regulation of tumour immunosurveillance (Ambrosino et al, 2007).…”

Section: Th Emop August 2008mentioning

confidence: 99%

Role of natural killer T lymphocytes during helminthic infection

2008

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Summary :Natural killer (NK)T cells are innate lymphocytes that release important amount of immunoregulatory cytokines (IFN-γ and/or IL-4) shortly after T cell receptor engagement by (glyco)lipid antigens presented by the CD1d molecules. Through this property, NKT cells play pivotal role in many physiopathologic situations. Here, we review the current knowledge of the functions and mechanisms of activation of NKT cells during infection, with a particular emphasis on helminthic infections. Recent findings suggest that, although dispensable for host resistance, NKT cells play part in the development of the acquired immune response and in the control of the pathology during murine schistosomiasis.

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Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis

Abstract: While Crohn disease (CD) has been clearly identified as a Th1 inflammation, the immunopathogenesis of its

Cited by 216 publications

References 45 publications

Proinflammatory cytokines and IL-10 in inflammatory bowel disease and colorectal cancer patients

Proinflammatory cytokines and IL-10 in inflammatory bowel disease and colorectal cancer patients

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Role of natural killer T lymphocytes during helminthic infection

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