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J Exp Med. 2016 Jan 11;213(1):123-38. doi: 10.1084/jem.20150519. Epub 2015 Dec 22.

CRTAM determines the CD4+ cytotoxic T lymphocyte lineage.

Author information

1
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.
2
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.
3
Laboratory for Cytokine Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
4
Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
5
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.
6
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho, Kyoto 606-8501, Japan.
7
WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
8
Immune Homeostasis Lab, Biomedial Research Institute, National Institute for Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8566, Japan.
9
Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
10
Department of Immunology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
11
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.
12
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.

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.

PMID:
26694968
PMCID:
PMC4710199
DOI:
10.1084/jem.20150519
[Indexed for MEDLINE]
Free PMC Article

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