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This study demonstrates that CD4+ T cells develop into antigen-specific memory T cells that can promote the terminal differentiation of memory B cells far more effectively than their naive T-cell counterparts. Memory T cell development requires the transcription factor B-cell lymphoma 6 (Bcl6), which is known to direct T-follicular helper (Tfh) cell differentiation. However, unlike Tfh cells, memory T cell development did not require germinal center B cells. Curiously, memory T cells that develop in the absence of cognate B cells cannot promote memory B-cell recall responses and this defect was accompanied by down-regulation of genes associated with homeostasis and activation and up-regulation of genes inhibitory for T-cell responses. Although memory T cells display phenotypic and genetic signatures distinct from Tfh cells, both had in common the expression of a group of genes associated with metabolic pathways. This gene expression profile was not shared to any great extent with naive T cells and was not influenced by the absence of cognate B cells during memory T cell development. These results suggest that memory T cell development is programmed by stepwise expression of gatekeeper genes through serial interactions with different types of antigen-presenting cells, first licensing the memory lineage pathway and subsequently facilitating the functional development of memory T cells. Finally, we identified Gdpd3 as a candidate genetic marker for memory T cells.<\/jats:p>","DOI":"10.1093\/intimm\/dxv071","type":"journal-article","created":{"date-parts":[[2015,12,29]],"date-time":"2015-12-29T20:44:36Z","timestamp":1451421876000},"page":"267-282","source":"Crossref","is-referenced-by-count":12,"title":["CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation"],"prefix":"10.1093","volume":"28","author":[{"given":"Tomohiro","family":"Kaji","sequence":"first","affiliation":[{"name":"Laboratory for Immunological Memory 1 , , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"},{"name":"RIKEN Research Center for Allergy and Immunology 1 , , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Hijikata","sequence":"additional","affiliation":[{"name":"Immunogenomics, RIKEN Research Center for Allergy and Immunology 2 , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Ishige","sequence":"additional","affiliation":[{"name":"Laboratory for Immunological Memory 1 , , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"},{"name":"RIKEN Research Center for Allergy and Immunology 1 , , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"},{"name":"Laboratory for Immune Regulation, RIKEN Center for Integrative Medical Sciences RCAI 3 , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshimori","family":"Kitami","sequence":"additional","affiliation":[{"name":"Cellular Bioenegetic Network, RIKEN Center for Integrative Medical Sciences RCAI (IMS-RCAI) 4 , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences RCAI 5 , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Ohara","sequence":"additional","affiliation":[{"name":"Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences RCAI 5 , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyuki","family":"Yanaka","sequence":"additional","affiliation":[{"name":"Department of Molecular and Applied Bioscience, Graduate School of Biosphere Science, Hiroshima University 6 , Higashi-Hiroshima, Hiroshima 739\u20138528 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Okada","sequence":"additional","affiliation":[{"name":"Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences RCAI 7 , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiko","family":"Shimoda","sequence":"additional","affiliation":[{"name":"Department of Dermatology, School of Medicine, University of California Davis 8 , Sacramento, CA 95817 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Laboratory for Immune Regulation, RIKEN Center for Integrative Medical Sciences RCAI 3 , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshitada","family":"Takemori","sequence":"additional","affiliation":[{"name":"Laboratory for Immunological Memory 1 , , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"},{"name":"RIKEN Research Center for Allergy and Immunology 1 , , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"},{"name":"Drug Discovery Antibody Platform Unit, RIKEN Center for Integrative Medical Sciences RCAI 9 , 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,12,29]]},"reference":[{"key":"2022071814470062000_CIT0001","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.immuni.2014.10.004","article-title":"T follicular helper cell differentiation, function, and roles in disease","volume":"41","author":"Crotty","year":"2014","journal-title":"Immunity"},{"key":"2022071814470062000_CIT0002","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev-immunol-031210-101400","article-title":"Follicular helper CD4 T cells (TFH)","volume":"29","author":"Crotty","year":"2011","journal-title":"Annu. 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