{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:25:00Z","timestamp":1790166300156,"version":"4.1.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2013,2,14]],"date-time":"2013-02-14T00:00:00Z","timestamp":1360800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Fas (CD95), a member of the tumor necrosis factor receptor superfamily, mediates apoptosis-inducing signals in its expressing cells, especially in self-reactive cells. We recently reported that Fas\u2212\/\u2212 mice with a BALB\/c background (BALB\/c Fas\u2212\/\u2212 mice) developed blepharitis with allergic inflammation that was accompanied by hyper-IgE production. Here, we found a novel type of immunocyte in the spleen of BALB\/c Fas\u2212\/\u2212 mice, which enhanced the production of IgE by B cells in the presence of IL-4 and CD40 signaling in vitro. The immunocyte did not express lineage markers but expressed Thy-1 and Sca-1 just like recently identified type 2 innate lymphoid cells, such as natural helper (NH) cells and nuocytes. However, they did not express c-Kit, IL-7R and IL-33R (T1\/ST2), important markers of type 2 innate lymphoid cells. Instead, our identified Lin\u2212Thy-1+Sca-1+ cells expressed IL-18R and secreted Th2 cytokines when co-cultured with B cells or when stimulated with IL-18 and IL-2. Moreover, we found essentially the same type of cells in BALB\/c wild-type mice as in BALB\/c Fas\u2212\/\u2212 mice, which enhanced IgE production in contact with B cells in vitro. These cells from BALB\/c wild-type mice expressed Fas and were sensitive to Fas-mediated apoptosis. Collectively, the newly identified Lin\u2212Thy-1+Sca-1+ cell, which we designated a F-NH cell (Fas-expressing natural helper cell), is a novel type 2 innate immunocyte with activity to enhance IgE production from B cells with the help of IL-4 and CD40 signaling. F-NH cells may play an important role in the development of chronic allergic inflammation.<\/jats:p>","DOI":"10.1093\/intimm\/dxs160","type":"journal-article","created":{"date-parts":[[2013,2,15]],"date-time":"2013-02-15T05:21:34Z","timestamp":1360905694000},"page":"373-382","source":"Crossref","is-referenced-by-count":19,"title":["Identification of a novel type 2 innate immunocyte with the ability to enhance IgE production"],"prefix":"10.1093","volume":"25","author":[{"given":"Ayumi","family":"Fukuoka","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University 1 , Kyoto 606\u20138501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizue","family":"Futatsugi-Yumikura","sequence":"additional","affiliation":[{"name":"Department of Immunology and Medical Zoology, Hyogo College of Medicine 2 , Nishinomiya, Hyogo 663\u20138501 , Japan"},{"name":"Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine 3 , Nishinomiya, Hyogo 663\u20138501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzuka","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University 1 , Kyoto 606\u20138501 , Japan"},{"name":"Division of Immune Regulation, Institute of Genome Research, University of Tokushima 5 Present address: , Tokushima 770\u20138503 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Kazama","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University 1 , Kyoto 606\u20138501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomonori","family":"Iyoda","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Graduate School of Biostudies, Kyoto University 4 , Kyoto 606\u20138501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Yoshimoto","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine 3 , Nishinomiya, Hyogo 663\u20138501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayo","family":"Inaba","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Graduate School of Biostudies, Kyoto University 4 , Kyoto 606\u20138501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Immunology and Medical Zoology, Hyogo College of Medicine 2 , Nishinomiya, Hyogo 663\u20138501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Yonehara","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University 1 , Kyoto 606\u20138501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,2,14]]},"reference":[{"key":"2022073002090974700_CIT0001","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0092-8674(00)81874-7","article-title":"Apoptosis by death factor","volume":"88","author":"Nagata","year":"1997","journal-title":"Cell"},{"key":"2022073002090974700_CIT0002","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/0092-8674(91)90614-5","article-title":"The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis","volume":"66","author":"Itoh","year":"1991","journal-title":"Cell"},{"key":"2022073002090974700_CIT0003","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S1359-6101(02)00024-2","article-title":"Death receptor Fas and autoimmune disease: from the original generation to therapeutic application of agonistic anti-Fas monoclonal antibody","volume":"13","author":"Yonehara","year":"2002","journal-title":"Cytokine Growth Factor Rev."},{"key":"2022073002090974700_CIT0004","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1093\/intimm\/8.3.423","article-title":"Functional significance of the Fas molecule in naive lymphocytes","volume":"8","author":"Senju","year":"1996","journal-title":"Int. Immunol."},{"key":"2022073002090974700_CIT0005","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/356314a0","article-title":"Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis","volume":"356","author":"Watanabe-Fukunaga","year":"1992","journal-title":"Nature"},{"key":"2022073002090974700_CIT0006","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1172\/JCI1817","article-title":"Loci predisposing to autoimmunity in MRL-Fas lpr and C57BL\/6-Faslpr mice","volume":"101","author":"Vidal","year":"1998","journal-title":"J. Clin. Invest."},{"key":"2022073002090974700_CIT0007","article-title":"Fas-deficiency in mice with the Balb\/c background induces blepharitis with allergic inflammation and hyper IgE production in conjunction with severe autoimmune disease","author":"Takahashi","journal-title":"Int Immunol"},{"key":"2022073002090974700_CIT0008","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/S1471-4906(01)01958-5","article-title":"Th2 responses without atopy: immunoregulation in chronic helminth infections and reduced allergic disease","volume":"22","author":"Yazdanbakhsh","year":"2001","journal-title":"Trends Immunol."},{"key":"2022073002090974700_CIT0009","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.4049\/jimmunol.174.2.1063","article-title":"Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production","volume":"174","author":"Gessner","year":"2005","journal-title":"J. Immunol."},{"key":"2022073002090974700_CIT0010","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/ni.1715","article-title":"Cytokine-secreting follicular T cells shape the antibody repertoire","volume":"10","author":"Reinhardt","year":"2009","journal-title":"Nat. Immunol."},{"key":"2022073002090974700_CIT0011","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/j.1365-2567.2011.03413.x","article-title":"Type 2 innate immune responses and the natural helper cell","volume":"132","author":"Koyasu","year":"2011","journal-title":"Immunology"},{"key":"2022073002090974700_CIT0012","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nature08636","article-title":"Innate production of Th2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells","volume":"463","author":"Moro","year":"2010","journal-title":"Nature"},{"key":"2022073002090974700_CIT0013","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1038\/nature08900","article-title":"Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity","volume":"464","author":"Neill","year":"2010","journal-title":"Nature"},{"key":"2022073002090974700_CIT0014","doi-asserted-by":"crossref","first-page":"11489","DOI":"10.1073\/pnas.1003988107","article-title":"Systemically dispersed innate IL-13-expressing cells in type 2 immunity","volume":"107","author":"Price","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2022073002090974700_CIT0015","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1038\/nature08901","article-title":"IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses","volume":"464","author":"Saenz","year":"2010","journal-title":"Nature"},{"key":"2022073002090974700_CIT0016","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.immuni.2005.09.015","article-title":"IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines","volume":"23","author":"Schmitz","year":"2005","journal-title":"Immunity"},{"key":"2022073002090974700_CIT0017","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.4049\/jimmunol.180.4.2443","article-title":"IL-33, a potent inducer of adaptive immunity to intestinal nematodes","volume":"180","author":"Humphreys","year":"2008","journal-title":"J. Immunol."},{"key":"2022073002090974700_CIT0018","doi-asserted-by":"crossref","first-page":"3451","DOI":"10.1073\/pnas.1201042109","article-title":"Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice","volume":"109","author":"Yasuda","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2022073002090974700_CIT0019","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.4049\/jimmunol.158.4.1541","article-title":"IFN-gamma-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12","volume":"158","author":"Kohno","year":"1997","journal-title":"J. Immunol."},{"key":"2022073002090974700_CIT0020","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1126\/science.275.5297.206","article-title":"Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme","volume":"275","author":"Gu","year":"1997","journal-title":"Science"},{"key":"2022073002090974700_CIT0021","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/77811","article-title":"IL-18 induction of IgE: dependence on CD4+ T cells, IL-4 and STAT6","volume":"1","author":"Yoshimoto","year":"2000","journal-title":"Nat. Immunol."},{"key":"2022073002090974700_CIT0022","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.4049\/jimmunol.164.5.2701","article-title":"IFN-gamma-inducing factor (IL-18) increases allergic sensitization, serum IgE, Th2 cytokines, and airway eosinophilia in a mouse model of allergic asthma","volume":"164","author":"Wild","year":"2000","journal-title":"J. Immunol."},{"key":"2022073002090974700_CIT0023","doi-asserted-by":"crossref","first-page":"13962","DOI":"10.1073\/pnas.96.24.13962","article-title":"IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils","volume":"96","author":"Yoshimoto","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2022073002090974700_CIT0024","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1146\/annurev.immunol.19.1.423","article-title":"Interleukin-18 regulates both Th1 and Th2 responses","volume":"19","author":"Nakanishi","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"2022073002090974700_CIT0025","doi-asserted-by":"crossref","first-page":"11931","DOI":"10.1073\/pnas.92.25.11931","article-title":"Defective IgE production by SJL mice is linked to the absence of CD4+, NK1.1+ T cells that promptly produce interleukin 4","volume":"92","author":"Yoshimoto","year":"1995","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2022073002090974700_CIT0026","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1073\/pnas.93.5.2131","article-title":"Enhanced and accelerated lymphoproliferation in Fas-null mice","volume":"93","author":"Adachi","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2022073002090974700_CIT0027","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1034\/j.1600-065X.2003.00047.x","article-title":"The role of CD95 in the regulation of peripheral T-cell apoptosis","volume":"193","author":"Krueger","year":"2003","journal-title":"Immunol. Rev."},{"key":"2022073002090974700_CIT0028","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/0092-8674(92)90029-C","article-title":"RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement","volume":"68","author":"Shinkai","year":"1992","journal-title":"Cell"},{"key":"2022073002090974700_CIT0029","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.immuni.2011.12.020","article-title":"Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation","volume":"36","author":"Halim","year":"2012","journal-title":"Immunity"},{"key":"2022073002090974700_CIT0030","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.cell.2008.10.048","article-title":"Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair","volume":"135","author":"Wilson","year":"2008","journal-title":"Cell"},{"key":"2022073002090974700_CIT0031","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1126\/science.1064081","article-title":"Physiological migration of hematopoietic stem and progenitor cells","volume":"294","author":"Wright","year":"2001","journal-title":"Science"},{"key":"2022073002090974700_CIT0032","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1084\/jem.20021701","article-title":"Nonredundant roles for CD1d-restricted natural killer T cells and conventional CD4+ T cells in the induction of immunoglobulin E antibodies in response to interleukin 18 treatment of mice","volume":"197","author":"Yoshimoto","year":"2003","journal-title":"J. Exp. Med."},{"key":"2022073002090974700_CIT0033","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1002\/eji.1830180716","article-title":"Interleukin 4 instructs uncommitted B lymphocytes to switch to IgG1 and IgE","volume":"18","author":"Bergstedt-Lindqvist","year":"1988","journal-title":"Eur. J. Immunol."},{"key":"2022073002090974700_CIT0034","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1600-065X.1988.tb00739.x","article-title":"The role of helper T cell products in mouse B cell differentiation and isotype regulation","volume":"102","author":"Coffman","year":"1988","journal-title":"Immunol. Rev."},{"key":"2022073002090974700_CIT0035","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1002\/eji.1830260332","article-title":"Activated B cells express functional Fas ligand","volume":"26","author":"Hahne","year":"1996","journal-title":"Eur. J. Immunol."},{"key":"2022073002090974700_CIT0036","doi-asserted-by":"crossref","first-page":"816","DOI":"10.4049\/jimmunol.147.3.816","article-title":"Eosinophil activation and T lymphocyte infiltration in allergen-induced late phase skin reactions and classical delayed-type hypersensitivity","volume":"147","author":"Gaga","year":"1991","journal-title":"J. Immunol."},{"key":"2022073002090974700_CIT0037","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.immuni.2005.06.011","article-title":"Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells","volume":"23","author":"Mukai","year":"2005","journal-title":"Immunity"},{"key":"2022073002090974700_CIT0038","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1111\/j.1365-2222.2004.1916.x","article-title":"Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma","volume":"34","author":"Holgate","year":"2004","journal-title":"Clin. Exp. Allergy"},{"key":"2022073002090974700_CIT0039","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.jaci.2004.11.053","article-title":"The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation","volume":"115","author":"Holgate","year":"2005","journal-title":"J. Allergy Clin. Immunol."}],"container-title":["International Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/25\/6\/373\/45192846\/intimm_25_6_373.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/25\/6\/373\/45192846\/intimm_25_6_373.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T15:11:39Z","timestamp":1688051499000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/intimm\/article\/25\/6\/373\/733718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,14]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2013,2,14]]},"published-print":{"date-parts":[[2013,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/intimm\/dxs160","relation":{},"ISSN":["1460-2377","0953-8178"],"issn-type":[{"value":"1460-2377","type":"electronic"},{"value":"0953-8178","type":"print"}],"subject":[],"published-other":{"date-parts":[[2013,6]]},"published":{"date-parts":[[2013,2,14]]}}}