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  • 1
    Abstract: Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth Heligmosomoides polygyrus drives rapid polyclonal expansion of Foxp3(+)Helios(+)CD4(+) thymic (t)Tregs in the lamina propria and mesenteric lymph nodes while Foxp3(+)Helios(-)CD4(+) peripheral (p)Treg expand more slowly. Notably, in partially resistant BALB/c mice parasite survival positively correlates with Foxp3(+)Helios(+)CD4(+) tTreg numbers. Boosting of Foxp3(+)Helios(+)CD4(+) tTreg populations by administration of recombinant interleukin-2 (rIL-2):anti-IL-2 (IL-2C) complex increased worm persistence by diminishing type-2 responsiveness in vivo, including suppression of alternatively activated macrophage and granulomatous responses at the sites of infection. IL-2C also increased innate lymphoid cell (ILC) numbers, indicating that Treg functions dominate over ILC effects in this setting. Surprisingly, complete removal of Tregs in transgenic Foxp3-DTR mice also resulted in increased worm burdens, with "immunological chaos" evident in high levels of the pro-inflammatory cytokines IL-6 and interferon-gamma. In contrast, worm clearance could be induced by anti-CD25 antibody-mediated partial depletion of early Treg, alongside increased T helper type 2 responses and without incurring pathology. These findings highlight the overarching importance of the early Treg response to infection and the non-linear association between inflammation and the prevailing Treg frequency.
    Type of Publication: Journal article published
    PubMed ID: 26286232
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  • 2
    Abstract: Infection with gastrointestinal helminths generates a dominant type 2 response among both adaptive (Th2) and innate (macrophage, eosinophil, and innate lymphoid) immune cell types. Two additional innate cell types, CD11c(high) dendritic cells (DCs) and basophils, have been implicated in the genesis of type 2 immunity. Investigating the type 2 response to intestinal nematode parasites, including Heligmosomoides polygyrus and Nippostrongylus brasiliensis, we first confirmed the requirement for DCs in stimulating Th2 adaptive immunity against these helminths through depletion of CD11c(high) cells by administration of diphtheria toxin to CD11c.DOG mice. In contrast, responsiveness was intact in mice depleted of basophils by antibody treatment. Th2 responses can be induced by adoptive transfer of DCs, but not basophils, exposed to soluble excretory-secretory products from these helminths. However, innate type 2 responses arose equally strongly in the presence or absence of CD11c(high) cells or basophils; thus, in CD11c.DOG mice, the alternative activation of macrophages, as measured by expression of arginase-1, RELM-alpha, and Ym-1 (Chi3L3) in the intestine following H. polygyrus infection or in the lung following N. brasiliensis infection, was unaltered by depletion of CD11c-expressing DCs and alveolar macrophages or by antibody-mediated basophil depletion. Similarly, goblet cell-associated RELM-beta in lung and intestinal tissues, lung eosinophilia, and expansion of innate lymphoid ("nuocyte") populations all proceeded irrespective of depletion of CD11c(high) cells or basophils. Thus, while CD11c(high) DCs initiate helminth-specific adaptive immunity, innate type 2 cells are able to mount an autonomous response to the challenge of parasite infection.
    Type of Publication: Journal article published
    PubMed ID: 22851746
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  • 3
    Publication Date: 2016-01-15
    Description: Helminth parasitic infections are a major global health and social burden. The host defence against helminths such as Nippostrongylus brasiliensis is orchestrated by type 2 cell-mediated immunity. Induction of type 2 cytokines, including interleukins (IL) IL-4 and IL-13, induce goblet cell hyperplasia with mucus production, ultimately resulting in worm expulsion. However, the mechanisms underlying the initiation of type 2 responses remain incompletely understood. Here we show that tuft cells, a rare epithelial cell type in the steady-state intestinal epithelium, are responsible for initiating type 2 responses to parasites by a cytokine-mediated cellular relay. Tuft cells have a Th2-related gene expression signature and we demonstrate that they undergo a rapid and extensive IL-4Ralpha-dependent amplification following infection with helminth parasites, owing to direct differentiation of epithelial crypt progenitor cells. We find that the Pou2f3 gene is essential for tuft cell specification. Pou2f3(-/-) mice lack intestinal tuft cells and have defective mucosal type 2 responses to helminth infection; goblet cell hyperplasia is abrogated and worm expulsion is compromised. Notably, IL-4Ralpha signalling is sufficient to induce expansion of the tuft cell lineage, and ectopic stimulation of this signalling cascade obviates the need for tuft cells in the epithelial cell remodelling of the intestine. Moreover, tuft cells secrete IL-25, thereby regulating type 2 immune responses. Our data reveal a novel function of intestinal epithelial tuft cells and demonstrate a cellular relay required for initiating mucosal type 2 immunity to helminth infection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gerbe, Francois -- Sidot, Emmanuelle -- Smyth, Danielle J -- Ohmoto, Makoto -- Matsumoto, Ichiro -- Dardalhon, Valerie -- Cesses, Pierre -- Garnier, Laure -- Pouzolles, Marie -- Brulin, Benedicte -- Bruschi, Marco -- Harcus, Yvonne -- Zimmermann, Valerie S -- Taylor, Naomi -- Maizels, Rick M -- Jay, Philippe -- 106122/Wellcome Trust/United Kingdom -- P30DC011735/DC/NIDCD NIH HHS/ -- England -- Nature. 2016 Jan 14;529(7585):226-30. doi: 10.1038/nature16527.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS, UMR-5203, Institut de Genomique Fonctionnelle, F-34094 Montpellier, France. ; INSERM, U1191, F-34094 Montpellier, France. ; Universite de Montpellier, F-34000 Montpellier, France. ; Institute of Immunology and Infection Research, School of Biological Sciences and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, UK. ; Monell Chemical Senses Center, 3500 Market Street, Philadelphia, Pennsylvania 19104, USA. ; Institut de Genetique Moleculaire de Montpellier, CNRS, UMR5535, F-34293 Montpellier, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Lineage ; Cell Proliferation ; Feedback, Physiological ; Female ; Goblet Cells/cytology/immunology ; Immunity, Mucosal/*immunology ; Interleukin-13/immunology ; Interleukin-17/immunology/metabolism ; Intestinal Mucosa/*cytology/*immunology/metabolism ; Male ; Mice ; Nippostrongylus/*immunology ; Octamer Transcription Factors/deficiency ; Parasites/*immunology ; Receptors, Interleukin-4/immunology ; Signal Transduction/immunology ; Stem Cells/cytology/immunology ; Strongylida Infections/immunology ; Th2 Cells/cytology/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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