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However, as such Notch signaling has not been detected in mature T cells, how Notch signaling contributes to their response in secondary lymphoid organs has not yet been fully defined. Here, we detected the marked expression of Dll4 on the stromal cells and the active fragment of Notch1 (Notch1 intracellular domain, N1ICD) in CD4+ T cells in the follicles of Peyer\u2019s patches (PPs). In addition, N1ICD-bearing T cells were found in the T-cell zone of PPs, especially in the transcription factor Foxp3+ regulatory T (Treg) cells, with slight expression of Dll4 on the stromal cells. These fragments disappeared in Dll4-deficient conditions. It was also found that Notch1- and Notch2-deficient T cells preferentially differentiated into Treg cells in PPs, but not CXCR5+PD-1+ follicular helper T (Tfh) cells. Moreover, these phenotypes were also observed in chimeric mice reconstituted with the control and T-cell-specific Notch1\/2-deficient bone marrow or Treg cells. These results demonstrated that Dll4-mediated Notch signaling in PPs is required for the efficient appearance of Tfh cells in a Treg cell-prone environment, which is common among the gut-associated lymphoid tissues, and is critical for the generation of Tfh-mediated germinal center B cells.<\/jats:p>","DOI":"10.1093\/intimm\/dxab032","type":"journal-article","created":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T03:12:41Z","timestamp":1623899561000},"page":"469-478","source":"Crossref","is-referenced-by-count":12,"title":["Notch signaling supports the appearance of follicular helper T cells in the Peyer\u2019s patches concomitantly with the reduction of regulatory T cells"],"prefix":"10.1093","volume":"33","author":[{"given":"Masaki","family":"Yazawa","sequence":"first","affiliation":[{"name":"Department of Immunology, Tokai University School of Medicine , Isehara, Kanagawa , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9592-2889","authenticated-orcid":false,"given":"Hiroyuki","family":"Hosokawa","sequence":"additional","affiliation":[{"name":"Department of Immunology, Tokai University School of Medicine , Isehara, Kanagawa , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8275-5594","authenticated-orcid":false,"given":"Maria","family":"Koizumi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Tokai University School of Medicine , Isehara, Kanagawa , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken-ichi","family":"Hirano","sequence":"additional","affiliation":[{"name":"Department of Immunology, Tokai University School of Medicine , Isehara, Kanagawa , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tokai University School of Medicine , Isehara, Kanagawa , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7685-6927","authenticated-orcid":false,"given":"Katsuto","family":"Hozumi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Tokai University School of Medicine , Isehara, Kanagawa , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,19]]},"reference":[{"key":"2022070116261827200_CIT0001","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/nrm2009","article-title":"Notch signalling: a simple pathway becomes complex","volume":"7","author":"Bray","year":"2006","journal-title":"Nat. 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Individual intestinal symbionts induce a distinct population of ROR\u03b3\u207a regulatory T cells","volume":"349","author":"Sefik","year":"2015","journal-title":"Science"},{"key":"2022070116261827200_CIT0019","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.immuni.2012.09.010","article-title":"T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development","volume":"37","author":"Ohkura","year":"2012","journal-title":"Immunity"},{"key":"2022070116261827200_CIT0020","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.immuni.2011.12.012","article-title":"Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells","volume":"36","author":"Miyao","year":"2012","journal-title":"Immunity"},{"key":"2022070116261827200_CIT0021","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/nm.3432","article-title":"Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis","volume":"20","author":"Komatsu","year":"2014","journal-title":"Nat. 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Structural basis for Notch1 engagement of Delta-like 4","volume":"347","author":"Luca","year":"2015","journal-title":"Science"},{"key":"2022070116261827200_CIT0054","doi-asserted-by":"crossref","first-page":"e50979","DOI":"10.7554\/eLife.50979","article-title":"Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice","volume":"9","author":"Hirano","year":"2020","journal-title":"Elife"}],"container-title":["International Immunology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/intimm\/advance-article-pdf\/doi\/10.1093\/intimm\/dxab032\/39308226\/dxab032.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/33\/9\/469\/44373019\/dxab032.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/33\/9\/469\/44373019\/dxab032.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T16:27:20Z","timestamp":1656692840000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/intimm\/article\/33\/9\/469\/6306513"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,19]]},"references-count":54,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,6,19]]},"published-print":{"date-parts":[[2021,8,23]]}},"URL":"https:\/\/doi.org\/10.1093\/intimm\/dxab032","relation":{},"ISSN":["1460-2377"],"issn-type":[{"value":"1460-2377","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,9,1]]},"published":{"date-parts":[[2021,6,19]]}}}