DOCK2 is required in T cell precursors for development of Vαa14 NK T cells

Mouse CD1d-restrieted V alpha 14 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 myoblasi city, is critical for lymphocyte migration and regulates T cell responsiveness through immunological synapse formation, yet its role in Va14 NKT cells remains unknown. We found that DOCK2 deficiency causes marked reduction of V alpha 14 NKT cells in the thymus, liver, and spleen. When alpha-galactosylceramide (alpha-GalCer), a ligand for V alpha 14 NKT cells, was administrated, cytokine production was scarcely detected in DOCK2-deficient mice, suggesting that DOCK2 deficiency primarily affects generation of Va14 NKT cells. Supporting this idea, staining with CD1d/alpha-GalCer tetramers revealed that CD44(-)NK1.1(-) V alpha 14 NKT cell precursors are severely reduced in the thymuses of DOCK2-deficient mice. In addition, studies using bone marrow chimeras indicated that development of Va14 NKT cells requires DOCK2 expression in T cell precursors, but not in APCs. These results indicate that DOCK2 is required for positive selection of Va14 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.