Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

McDermott, Jacqueline; Humphreys, Neil; Forman, Simon; Donaldson, Debra D.; Grencis, Richard K.

doi:10.4049/jimmunol.175.5.3207

Cited by 84 publications

(79 citation statements)

References 50 publications

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“…Taken together, our results indicate that the IL-13-producing DX5 + cells are NK cells, since they expressed IL-2Rb, CD11b and Ly49C but not FceRI, c-kit or TCR. It has consistently been reported that NK cells are an important source of IL-13 in vitro and in vivo [17,46,47]. In particular, our findings demonstrate that NK cells express IL-13 as well as IFN-c in vivo during infectious disease.…”

supporting

confidence: 80%

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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supporting

confidence: 80%

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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“…Intestinal pathology in our model infection appeared as increased cellular infiltration of the lamina propria and a disturbed architecture of the intestinal epithelium with villus atrophy and crypt hyperplasia. For infections with T. spiralis it has been shown that IL-13 is responsible for villus atrophy as well as crypt and goblet cell hyperplasia [35]. Hence, we speculate that the increased IL-13 response in Figure 6.…”

Section: Discussionmentioning

confidence: 78%

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3⁺ cells

et al. 2009

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Here, we show that Treg limit intestinal pathology during nematode infection and that they control the onset and magnitude of the anti-parasitic Th Th2 response. Using mice expressing the diptheria toxin receptor under the control of the foxp3 locus, we removed Foxp3 1 Treg during the early phase of infection with Heligmosomoides polygyrus bakeri. Depletion of Treg in infected animals did not affect adult worm burden, but led to increased pathology at the site of infection. Infected, depleted mice displayed higher frequencies of activated CD4 1 T cells and increased levels of the Th2 cytokines IL-4 and IL-13. The stronger parasite-specific Th2 response was accompanied by higher levels of IL-10. Only a moderate change in Th1 (IFN-c) reactivity was detected in worm-infected, Treg-depleted mice. Furthermore, we detected an accelerated onset of parasite-specific Th2 and IL-10 responses in the transient absence of Foxp3 1 Treg. However, adult worm burdens were not affected by the increased Th2-reactivity in Treg-depleted mice. Hence, our data show that Treg restrict the onset and strength of Th2 responses during intestinal worm infection, while increasing primary Th2 responses does not necessarily lead to killing of larvae or accelerated expulsion of adult worms.Key words: Foxp3 . Nematode . Pathology . Th2 response . Treg IntroductionParasitic worms are the most potent inducers of highly polarized Th cell type 2 (Th2) responses. Helminth infections tend to be long lasting and are often associated with insufficient immunity to re-infection [1,2]. Chronic infections favor immunosuppression, the so-called modulated Th2-response, associated with poor parasite-specific reactivity alongside with the strong production of anti-inflammatory cytokines, such as . This helminth-induced immunosuppression may spill over to bystander antigens [3], downmodulate reactivity against other pathogens [4] and impair vaccination efficacy [5]. However, such effects can be beneficial by downregulating inflammatory reactions to allergens and inflammatory disorders of the intestinal tract. Studies in animal models showed that helminths can suppress airway hyperreactivity and colitis [6][7][8] and nematodes have been used to efficiently treat human inflammatory bowel disease in clinical trials [9,10]. 3066In animal models, the beneficial effects of nematode infections on inflammatory disorders were associated with the presence of Treg populations [6,11,12]. However, it is not yet clear whether such Treg suppress anti-parasite immune reactivity and thus contribute to survival and well-being of the worms, or whether they predominantly dampen immunopathology. Several studies investigated the role of Treg in infections with helminths or other parasites and yielded in diverging conclusions (reviewed in [1] and [13]). There is evidence that certain parasites depend on Treg action for their persistence [14][15][16][17]. Other species profit more indirectly from Treg circuits, which control infectioninduced pathology [18][19][20].In a previous study ...

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“…Indeed, these treated mice showed an elevation in NK cells within the MLN. These cells are a well-characterized source of IFN-␥ (37) and have previously been demonstrated in SCID mice to be responsible for the disruption of intestinal tissue architecture in the context of infection with the intestinal helminth Trichinella spiralis, although in this case via the cytokine IL-13 (38). Whether IL-33's ability to alter inflamed tissue in a non-T cell manner and the direct effects this cytokine has on T cell polarization are functions that influence one another remains to be resolved.…”

Section: Discussionmentioning

confidence: 99%

IL-33, a Potent Inducer of Adaptive Immunity to Intestinal Nematodes

Humphreys

Hepworth

et al. 2008

The Journal of Immunology

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IL-33 (IL-1F11) binds ST2 (IL-1R4), both of which are associated with optimal CD4+ Th2 polarization. Exogenous IL-33 drives induction of Th2-associated cytokines and associated pathological changes within the gut mucosa. Th2 polarization is also a prerequisite to expulsion of the intestinal-dwelling nematode Trichuris muris. In this study, we demonstrate that IL-33 mRNA is expressed early during parasite infection and susceptible mice can be induced to expel the parasite by a regime of exogenous IL-33 administration. IL-33 prevents an inappropriate parasite-specific Th1-polarized response and induces IL-4, IL-9, and IL-13. This redirection requires the presence of T cells and must occur at the initiation of the response to the pathogen. Interestingly, exogenous IL-33 also induced thymic stromal lymphopoietin mRNA within the infected caecum, an epithelial cell-restricted cytokine essential for the generation of Th2-driven parasite immunity. IL-33 also acts independently of T cells, altering intestinal pathology in chronically infected SCID mice, leading to an increased crypt length and intestinal epithelial cell proliferation, but reducing goblet cell hyperplasia. Thus, the ability of IL-33 to induce Th2 responses has functional relevance in the context of intestinal helminth infection, particularly during the initiation of the response.

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Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

Cited by 84 publications

References 50 publications

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

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

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3⁺ cells

IL-33, a Potent Inducer of Adaptive Immunity to Intestinal Nematodes

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Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

Cited by 84 publications

References 50 publications

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

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

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells

IL-33, a Potent Inducer of Adaptive Immunity to Intestinal Nematodes

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Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3⁺ cells