{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:57:32Z","timestamp":1790125052033,"version":"4.0.1"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2009,9,1]],"date-time":"2009-09-01T00:00:00Z","timestamp":1251763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Host gender has previously been identified as a determining factor in the resolution of Trichuris muris infection in mice lacking IL-4 (IL-4KO BALB\/c). Worm expulsion in these mice is delayed, but occurs in females. In this study we were able to demonstrate delayed expulsion occurs at day 26 post infection and is associated with the production of the key Th2-associated cytokine IL-13 by both CD4+ T cells and an auxiliary DX5+ NK cell source, as well as a concurrent reduction in proinflammatory cytokines. NK cell number was comparably increased in both sexes, but NK cells from male mice were found to express higher levels of the chemokine receptor CXCR3. Depletion of CD4+ T cells completely prevented parasite expulsion, whereas loss of NK cells resulted in a mild, but significant delay. Furthermore, IL-18 is a cytokine with the capacity to enhance both Th1 and Th2 responses found to be dispensable for worm expulsion in female mice but was a key factor for the suppression of the Th2 response in male IL-4KO mice. In contrast neutralization of IFN-\u03b3 resulted in a complete restoration of typical wild-type BALB\/c expulsion kinetics. This study sheds further light on the role of accessory NK cells in supplementing the IL-13-driven immune response when normal Th2 immunity is disrupted, and further identifies host gender as a key factor in determining the generation of \u201cNK cell help\u201d.<\/jats:p>","DOI":"10.4049\/jimmunol.0900577","type":"journal-article","created":{"date-parts":[[2009,8,19]],"date-time":"2009-08-19T22:10:04Z","timestamp":1250719804000},"page":"3906-3914","source":"Crossref","is-referenced-by-count":26,"title":["Disruption of Th2 Immunity Results in a Gender-Specific Expansion of IL-13 Producing Accessory NK Cells during Helminth Infection"],"prefix":"10.1093","volume":"183","author":[{"given":"Matthew R","family":"Hepworth","sequence":"first","affiliation":[{"name":"Faculty of Life Sciences, University of Manchester , Manchester,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard K","family":"Grencis","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences, University of Manchester , Manchester,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,9,15]]},"reference":[{"key":"2026012811261955100_R1","first-page":"61","article-title":"The influence of genes mapping within the major histocompatibility complex on resistance to Trichuris-muris infections in mice.","volume-title":"Parasitology","year":"1990"},{"key":"2026012811261955100_R2","first-page":"1463","article-title":"Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion.","volume-title":"Science","year":"2005"},{"key":"2026012811261955100_R3","first-page":"3453","article-title":"A critical role for IL-13 in resistance to intestinal nematode infection.","volume-title":"J. Immunol.","year":"1998"},{"key":"2026012811261955100_R4","first-page":"2083","article-title":"Gastrointestinal nematode expulsion in IL-4 knockout mice is IL-13 dependent.","volume-title":"Eur. J. Immunol.","year":"2000"},{"key":"2026012811261955100_R5","first-page":"247","article-title":"Hormonal and immunological mechanisms mediating sex differences in parasite infection.","volume-title":"Parasite Immunol.","year":"2004"},{"key":"2026012811261955100_R6","first-page":"1187","article-title":"IL-18 stimulates IL-13-mediated IFN-\u03b3-sensitive host resistance in vivo.","volume-title":"Eur. J. Immunol.","year":"2006"},{"key":"2026012811261955100_R7","first-page":"4250","article-title":"IL-13-mediated worm expulsion is B7 independent and IFN-\u03b3 sensitive.","volume-title":"J. Immunol.","year":"2000"},{"key":"2026012811261955100_R8","first-page":"51","article-title":"IL-13 production by NK cells: IL-13-producing NK and T cells are present in vivo in the absence of IFN-\u03b3.","volume-title":"J. Immunol.","year":"1999"},{"key":"2026012811261955100_R9","first-page":"3207","article-title":"Intraepithelial NK cell-derived IL-13 induces intestinal pathology associated with nematode infection.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012811261955100_R10","first-page":"629","article-title":"Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells.","volume-title":"Immunity","year":"2002"},{"key":"2026012811261955100_R11","first-page":"582","article-title":"Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.","volume-title":"Nat. Med.","year":"2003"},{"key":"2026012811261955100_R12","first-page":"5070","article-title":"IL-18 is a potent coinducer of IL-13 in NK and T cells: a new potential role for IL-18 in modulating the immune response.","volume-title":"J. Immunol.","year":"1999"},{"key":"2026012811261955100_R13","first-page":"355","article-title":"Interleukin (IL)-18 promotes the development of chronic gastrointestinal helminth infection by downregulating IL-13.","volume-title":"J. Exp. Med.","year":"2001"},{"key":"2026012811261955100_R14","first-page":"88","article-title":"Cloning of a new cytokine that induces IFN-\u03b3 production by T cells.","volume-title":"Nature","year":"1995"},{"key":"2026012811261955100_R15","first-page":"1627","article-title":"Cutting edge: priming of NK cells by IL-18.","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012811261955100_R16","first-page":"1395","article-title":"Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions.","volume-title":"J. Exp. Med.","year":"2009"},{"key":"2026012811261955100_R17","first-page":"487","article-title":"Efficient targeting of the IL-4 gene in a BALB\/c embryonic stem cell line.","volume-title":"Transgenic Res.","year":"1996"},{"key":"2026012811261955100_R18","first-page":"427","article-title":"The development of the early larval stages of Trichuris muris in the albino laboratory mouse.","volume-title":"J. Helminthol.","year":"1969"},{"key":"2026012811261955100_R19","first-page":"255","article-title":"The Trichuris muris system: a paradigm of resistance and susceptibility to intestinal nematode infection.","volume-title":"Adv. Parasitol.","year":"2004"},{"key":"2026012811261955100_R20","first-page":"339","article-title":"A distinct role for interleukin-13 in Th2-cell-mediated immune responses.","volume-title":"Curr. Biol.","year":"1998"},{"key":"2026012811261955100_R21","first-page":"144","article-title":"Trichuris muris: Host intestinal epithelial cell hyperproliferation during chronic infection is regulated by interferon-\u03b3.","volume-title":"Exp. Parasitol.","year":"1999"},{"key":"2026012811261955100_R22","first-page":"4967","article-title":"STAT6-dependent differentiation and production of IL-5 and IL-13 in murine NK2 cells.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012811261955100_R23","first-page":"507","article-title":"Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite.","volume-title":"J. Exp. Med.","year":"2004"},{"key":"2026012811261955100_R24","first-page":"3723","article-title":"Genomic characterization of a \u03b3-interferon-inducible gene (IP-10) and identification of an interferon-inducible hypersensitive site.","volume-title":"Mol. Cell Biol.","year":"1987"},{"key":"2026012811261955100_R25","first-page":"3147","article-title":"IL-18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background.","volume-title":"Eur. J. Immunol.","year":"2000"},{"key":"2026012811261955100_R26","first-page":"4780","article-title":"IL-33 induces antigen-specific IL-5+ T cells and promotes allergic-induced airway inflammation independent of IL-4.","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012811261955100_R27","first-page":"1341","article-title":"Transforming growth factor-\u03b2\u2018reprograms\u2019 the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset.","volume-title":"Nat. Immunol.","year":"2008"},{"key":"2026012811261955100_R28","first-page":"1837","article-title":"IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells.","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2026012811261955100_R29","first-page":"2616","article-title":"IL-4-independent regulation of in vivo IL-9 expression.","volume-title":"J. Immunol.","year":"1997"},{"key":"2026012811261955100_R30","first-page":"189","article-title":"Sex-hormones and the course of parasitic infection.","volume-title":"Parasitol. Today","year":"1988"},{"key":"2026012811261955100_R31","first-page":"575","article-title":"The role of TNF-\u03b1 in Trichuris muris infection I: influence of TNF-\u03b1 receptor usage, gender and IL-13.","volume-title":"Parasite Immunol.","year":"2007"},{"key":"2026012811261955100_R32","first-page":"111","article-title":"The IL-2 receptor \u03b2 subunit is absolutely required for mediating the IL-2-induced activation of NK activity and proliferative activity of human large granular lymphocytes.","volume-title":"Immunology","year":"1990"},{"key":"2026012811261955100_R33","first-page":"1260","article-title":"Induced recruitment of NK cells to lymph nodes provides IFN-\u03b3 for TH1 priming.","volume-title":"Nat. Immunol.","year":"2004"},{"key":"2026012811261955100_R34","first-page":"4716","article-title":"IFN-\u03b3 acts on T cells to induce NK cell mobilization and accumulation in target organs.","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012811261955100_R35","first-page":"5235","article-title":"The interferon-stimulated response element and a kappa B site mediate synergistic induction of murine IP-10 gene transcription by IFN-\u03b3 and TNF-\u03b1.","volume-title":"J. Immunol.","year":"1995"},{"key":"2026012811261955100_R36","first-page":"535","article-title":"Treatment of monocytes with interleukin (IL)-12 plus IL-18 stimulates survival, differentiation and the production of CXC chemokine ligands (CXCL)8, CXCL9 and CXCL10.","volume-title":"Clin. Exp. Immunol.","year":"2006"},{"key":"2026012811261955100_R37","first-page":"338","article-title":"IL-18 enhances IFN-\u03b3-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes.","volume-title":"Eur. J. Immunol.","year":"2007"},{"key":"2026012811261955100_R38","first-page":"6320","article-title":"Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1998"},{"key":"2026012811261955100_R39","first-page":"97","article-title":"Propionibacterium acnes treatment diminishes CD4+ NK1.1+ T cells but induces type I T cells in the liver by induction of IL-12 and IL-18 production from Kupffer cells.","volume-title":"J. Immunol.","year":"1997"},{"key":"2026012811261955100_R40","first-page":"6829","article-title":"IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn\u2019s disease: expression and localization in intestinal mucosal cells.","volume-title":"J. Immunol.","year":"1999"},{"key":"2026012811261955100_R41","first-page":"2256","article-title":"Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1\u03b2 are differentially regulated in human blood mononuclear cells and mouse spleen cells.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1999"},{"key":"2026012811261955100_R42","first-page":"3231","article-title":"Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC): DC-derived IL-18 enhances IL-12-dependent Th1 development.","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2026012811261955100_R43","first-page":"S370","article-title":"Interleukin-18 and host defense against infection.","volume-title":"J. Infect. Dis.","year":"2003"},{"key":"2026012811261955100_R44","first-page":"71","article-title":"Cytokine expression by murine DX5+ cells in response to IL-12, IL-18, or the combination of IL-12 and IL-18.","volume-title":"Cell. Immunol.","year":"2001"},{"key":"2026012811261955100_R45","first-page":"2553","article-title":"IL-18 regulates intestinal mastocytosis and Th2 cytokine production independently of IFN-\u03b3 during Trichinella spiralis infection.","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012811261955100_R46","first-page":"767","article-title":"Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris-infected mice.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2000"},{"key":"2026012811261955100_R47","first-page":"2549","article-title":"Sex-determined resistance to Toxoplasma gondii is associated with temporal differences in cytokine production.","volume-title":"Infect. Immun.","year":"1995"},{"key":"2026012811261955100_R48","first-page":"382","article-title":"Critical role of IL-17 receptor signaling in acute TNBS-induced colitis.","volume-title":"Inflamm. Bowel Dis.","year":"2006"},{"key":"2026012811261955100_R49","first-page":"552","article-title":"Epithelial-cell-intrinsic IKK-\u03b2 expression regulates intestinal immune homeostasis.","volume-title":"Nature","year":"2007"},{"key":"2026012811261955100_R50","first-page":"229","article-title":"IL-17A-producing neutrophil-regulatory Tn lymphocytes.","volume-title":"Immunol. Res.","year":"2006"},{"key":"2026012811261955100_R51","first-page":"1133","article-title":"A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.","volume-title":"Nat. Immunol.","year":"2005"},{"key":"2026012811261955100_R52","first-page":"4709","article-title":"Goblet cell-derived resistin-like molecule \u03b2 augments CD4+ T cell production of IFN-\u03b3 and infection-induced intestinal inflammation.","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012811261955100_R53","first-page":"13596","article-title":"RELM\u03b2\/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2004"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/6\/3906\/62692441\/9679.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/6\/3906\/62692441\/9679.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T16:28:54Z","timestamp":1769617734000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/183\/6\/3906\/8053529"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,9]]},"references-count":53,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2009,9,15]]},"published-print":{"date-parts":[[2009,9,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0900577","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,9]]},"published":{"date-parts":[[2009,9]]}}}