DOCK2 is required in T cell precursors for development of Valpha14 NK T cells.
Mouse CD1d-restricted Valpha14 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 Valpha14 NKT cells remains unknown. We found that DOCK2 deficiency causes marked reduction of Valpha14 NKT cells in the thymus, liver, and spleen. When alpha-galactosylceramide (alpha-GalCer), a ligand for Valpha14 NKT cells, was administrated, cytokine production was scarcely detected in DOCK2-deficient mice, suggesting that DOCK2 deficiency primarily affects generation of Valpha14 NKT cells. Supporting this idea, staining with CD1d/alpha-GalCer tetramers revealed that CD44- NK1.1- Valpha14 NKT cell precursors are severely reduced in the thymuses of DOCK2-deficient mice. In addition, studies using bone marrow chimeras indicated that development of Valpha14 NKT cells requires DOCK2 expression in T cell precursors, but not in APCs. These results indicate that DOCK2 is required for positive selection of Valpha14 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.
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Yuya
Y
Kunisaki
Yoshihiko
Y
Tanaka
Terukazu
T
Sanui
Ayumi
A
Inayoshi
Mayuko
M
Noda
Toshinori
T
Nakayama
Michishige
M
Harada
Masaru
M
Taniguchi
Takehiko
T
Sasazuki
Yoshinori
Y
Fukui
D000818:Animals; D017951:Antigen Presentation; D018949:Antigens, CD1 / Q000235:genetics / Q000378:metabolism; D055610:Antigens, CD1d; D005260:Female; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005699:Galactosylceramides / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D018949:Antigens, CD1; D055610:Antigens, CD1d; C471356:DOCK2 protein, mouse; D020690:GTPase-Activating Proteins; D005699:Galactosylceramides; D020662:Guanine Nucleotide Exchange Factors; D016693:Receptors, Antigen, T-Cell, alpha-beta; C493154:alpha-galactosylceramide