title: CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation.
abstract: Memory CD4(+) T cells promote protective humoral immunity; however, how memory T cells acquire this activity remains unclear. 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.
authors.affiliation: Laboratory for Immunological Memory, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaji
authors.affiliation: Immunogenomics, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hijikata
authors.affiliation: Laboratory for Immunological Memory, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan Laboratory for Immune Regulation, RIKEN Center for Integrative Medical Sciences RCAI, 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ishige
authors.affiliation: Cellular Bioenegetic Network, RIKEN Center for Integrative Medical Sciences RCAI (IMS-RCAI), 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Toshimori
authors.initials: T
authors.lastname: Kitami
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences RCAI, 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences RCAI, 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Department of Molecular and Applied Bioscience, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8528, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yanaka
authors.affiliation: Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences RCAI, 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Dermatology, School of Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: Michiko
authors.initials: M
authors.lastname: Shimoda
authors.affiliation: Laboratory for Immune Regulation, RIKEN Center for Integrative Medical Sciences RCAI, 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Laboratory for Immunological Memory, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan Drug Discovery Antibody Platform Unit, RIKEN Center for Integrative Medical Sciences RCAI, 1-7-22, Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan toshitada.takemori@riken.jp.
authors.forename: Toshitada
authors.initials: T
authors.lastname: Takemori
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000276:immunology*; D007121:Immunocompetence; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D059467:Transcriptome
chemical_list: D015704:CD4 Antigens; D051560:Proto-Oncogene Proteins c-bcl-6; D010727:Phosphoric Diester Hydrolases; C038133:glycerophosphodiester phosphodiesterase
keywords: Bcl6 (B-cell lymphoma 6); CD4 memory T-cell development; T-follicular helper cells; cognate interaction with non-GC B cells; memory B-cell recall response; stepwise transcriptional regulation