The Journal of Experimental Medicine
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Published 15 December 2003. doi:10.1084/jem.20030958
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© Rockefeller University Press, 0022-1007/2003/12/1829 $5.00
The Journal of Experimental Medicine, Volume 198, Number 12, 1829-1839

CD226 (DNAM-1) Is Involved in Lymphocyte Function–associated Antigen 1 Costimulatory Signal for Naive T Cell Differentiation and Proliferation

Kazuko Shibuya1,3, Jun Shirakawa1,4, Tomie Kameyama1, Shin-ichiro Honda1, Satoko Tahara-Hanaoka1, Akitomo Miyamoto1, Masafumi Onodera4, Takayuki Sumida3, Hiromitsu Nakauchi4, Hiroyuki Miyoshi2,4 and Akira Shibuya1,4,5

1 Laboratory for Immune Receptor, RIKEN Research Center for Allergy and Immunology
2 Subteam for Manipulation of Cell Fate, BioResource Center, RIKEN Tsukuba Institute, Ibaraki 305-0074, Japan
3 Department of Rheumatology, Institute of Clinical Medicine
4 Department of Immunology, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki 305-8575, Japan
5 PRESTO, Japan Science and Technology Corporation, Saitama 332-0012, Japan

Address correspondence to Akira Shibuya, Laboratory for Immune Receptor, RIKEN Research Center for Allergy and Immunology, 3-1-1 Koyadai, Ibaraki 305-0074, Japan. Phone: 81-298-36-9174; Fax: 81-298-36-9175; email: ashibuya{at}rtc.riken.go.jp

Upon antigen recognition by the T cell receptor, lymphocyte function–associated antigen 1 (LFA-1) physically associates with the leukocyte adhesion molecule CD226 (DNAM-1) and the protein tyrosine kinase Fyn. We show that lentiviral vector-mediated mutant (Y-F322) CD226 transferred into naive CD4+ helper T cells (Ths) inhibited interleukin (IL)-12–independent Th1 development initiated by CD3 and LFA-1 ligations. Moreover, proliferation induced by LFA-1 costimulatory signal was suppressed in mutant (Y-F322) CD226-transduced naive CD4+ and CD8+ T cells in the absence of IL-2. These results suggest that CD226 is involved in LFA-1–mediated costimulatory signals for triggering naive T cell differentiation and proliferation. We also demonstrate that although LFA-1, CD226, and Fyn are polarized at the immunological synapse upon stimulation with anti-CD3 in CD4+ and CD8+ T cells, lipid rafts are polarized in CD4+, but not CD8+, T cells. Moreover, proliferation initiated by LFA-1 costimulatory signal is suppressed by lipid raft disruption in CD4+, but not CD8+, T cells, suggesting that the LFA-1 costimulatory signal is independent of lipid rafts in CD8+ T cells.

Key Words: LFA-1 • CD226 • costimulatory molecules • lentiviral vector • naive T cells

H. Nakauchi's present address is Laboratory of Stem Cell Therapy, Center for Experimental Medicine, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

Abbreviations used in this paper: CB, cord blood; cPPT, central polypurine tract; CTS, central termination sequence; ICAM, intercellular adhesion molecule; IRES, internal ribosome entry site; MßCD, methyl-ß-cyclodextrin; MOI, multiplicity of infection; PB, peripheral blood; SIN, self-inactivating; WPRE, woodchuck hepatitis virus posttranscriptional regulatory element.


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