title: CRTAM determines the CD4+ cytotoxic T lymphocyte lineage.
abstract: Naive T cells differentiate into various effector T cells, including CD4(+) helper T cell subsets and CD8(+) cytotoxic T cells (CTL). Although cytotoxic CD4(+) T cells (CD4 +: CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4(+) T cells that express class I-restricted T cell-associated molecule (CRTAM) upon activation possesses the characteristics of both CD4(+) and CD8(+) T cells. CRTAM(+) CD4(+) T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM(+) T cells are the precursor of CD4(+)CTL. Indeed, ectopic expression of CRTAM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4(+)CTL and IFN-γ production requires CRTAM-mediated intracellular signaling. CRTAM(+) T cells traffic to mucosal tissues and inflammatory sites and developed into CD4(+)CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRTAM is critical to instruct the differentiation of CD4(+)CTL through the induction of Eomes and CTL-related gene.
authors.affiliation: Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan Department of Immunology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Mohamed El Sherif Gadelhaq
authors.initials: Mel S
authors.lastname: Badr
authors.affiliation: Laboratory for Cytokine Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Miyauchi
authors.affiliation: Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Ishihara
authors.affiliation: Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Onishi
authors.affiliation: Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Zijin
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho, Kyoto 606-8501, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ike
authors.affiliation: Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Takumi
authors.affiliation: Immune Homeostasis Lab, Biomedial Research Institute, National Institute for Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8566, Japan.
authors.forename: Noriko M
authors.initials: NM
authors.lastname: Tsuji
authors.affiliation: Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Immunology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Katakai
authors.affiliation: Laboratory for Cytokine Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, Chiba 278-0022, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan takashi.saito@riken.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*
chemical_list: D007136:Immunoglobulins; D020825:T-Box Domain Proteins; C408522:class-I restricted T cell-associated molecule; D007371:Interferon-gamma