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

Kazuko Shibuya^1,3, Jun Shirakawa^1,4, Tomie Kameyama¹, Shin-ichiro Honda¹, Satoko Tahara-Hanaoka¹, Akitomo Miyamoto¹, Masafumi Onodera⁴, Takayuki Sumida³, Hiromitsu Nakauchi⁴, Hiroyuki Miyoshi^2,4 and Akira Shibuya^1,4,5

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

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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