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DOCK2 Is Required in T Cell Precursors for Development of V14 NK T Cells¹

Yuya Kunisaki^*, Yoshihiko Tanaka^*, Terukazu Sanui^*, Ayumi Inayoshi^*,, Mayuko Noda^*,, Toshinori Nakayama, Michishige Harada, Masaru Taniguchi, Takehiko Sasazuki^¶ and Yoshinori Fukui^2,*,

^* Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan; Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan; and ^¶ International Medical Center of Japan, Tokyo, Japan

Mouse CD1d-restricted V14 NKT cells are a unique subset of lymphocytes, which play important roles in immune regulation, tumor surveillance and host defense against pathogens. DOCK2, a mammalian homolog of Caenorhabditis elegans CED-5 and Drosophila melanogaster myoblast city, is critical for lymphocyte migration and regulates T cell responsiveness through immunological synapse formation, yet its role in V14 NKT cells remains unknown. We found that DOCK2 deficiency causes marked reduction of V14 NKT cells in the thymus, liver, and spleen. When -galactosylceramide (-GalCer), a ligand for V14 NKT cells, was administrated, cytokine production was scarcely detected in DOCK2-deficient mice, suggesting that DOCK2 deficiency primarily affects generation of V14 NKT cells. Supporting this idea, staining with CD1d/-GalCer tetramers revealed that CD44^–NK1.1^– V14 NKT cell precursors are severely reduced in the thymuses of DOCK2-deficient mice. In addition, studies using bone marrow chimeras indicated that development of V14 NKT cells requires DOCK2 expression in T cell precursors, but not in APCs. These results indicate that DOCK2 is required for positive selection of V14 NKT cells in a cell-autonomous manner, thereby suggesting that avidity-based selection also governs development of this unique subset of lymphocytes in the thymus.

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