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* Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan;
Division of Pathology and Disease Regulation, Shiga University of Medical Science, Otsu, Shiga, Japan;
Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan;
Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan;
¶ Department of Biochemistry and Molecular Biology, Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan;
|| Department of Molecular Biology, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari, Osaka, Japan; and
# Laboratory of Cell Signaling, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
In vivo immune response is triggered in the lymph node, where lymphocytes for entry into, retention at, and migration to effector sites are dynamically regulated. The molecular mechanism underlying retention regulation is the key to elucidating in vivo regulation of immune response. In this study, we describe the function of the adhesion molecule class I-restricted T cell-associated molecule (CRTAM) in regulating CD8+ T cell retention within the lymph node and eventually effector function. We previously identified CRTAM as a receptor predominantly expressed on activated CD8+ T cells, and nectin-like molecule-2 (Necl2) as its ligand. In vivo function of CRTAM-Necl2 interaction was analyzed by generating CRTAM–/– mice. CRTAM–/– mice exhibited reduced protective immunity against viral infection and impaired autoimmune diabetes induction in vivo. Although Ag-specific CRTAM–/– CD8+ T cells showed normal CTL functions in vitro, their number in the draining lymph node was reduced. Because CRTAM+ T cells bound efficiently to Necl2-expressing CD8+ dendritic cells (DCs) that reside in T cell area of lymph node, CRTAM may induce retention by binding to CD8+ DCs at the late stage of activation before proliferation. The CRTAM-mediated late interaction with DCs induced retention of activated CD8+ T cells in an Ag-independent fashion, and this possibly resulted in effective CTL development in the draining lymph node.
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1 This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
2 Current address: Division of Molecular Immunity, Research Center for Infection Network, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
3 Address correspondence and reprint requests to Dr. Takashi Saito, Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan. E-mail address: saito{at}rcai.riken.jp
4 Abbreviations used in this paper: S1P, sphingosine-1-phosphatase; DC, dendritic cell; CRTAM, class I-restricted T cell-associated molecule; ES, embryonic stem; KO, knockout; LN, lymph node; mOVA, membrane-bound OVA; Necl2, nectin-like molecule-2; NP, nuclear protein; RIP, rat insulin promoter; S1P1, S1P receptor-1; Tg, transgenic; WT, wild type.
5 The online version of this article contains supplemental material.
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