Essential role of Rap signal in pre-TCR-mediated {beta}-selection checkpoint in {alpha}{beta} T-cell development

Kohei Kometani, Masaki Moriyama, Yasuhiro Nakashima, Yoshinori Katayama, Shu Fang Wang, Shou Yamasaki, Takashi Saito, Masakazu Hattori, Nagahiro Minato

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    Abstract

    We demonstrate that lck promoter-driven conditional expression of transgenic SPA-1, a Rap GTPase-activation protein, causes a profound defect of αβ T-cell development at the CD4/CD8 double-negative (DN) stage due to enhanced cell death without affecting γδ T-cell development. The effect was specific to the DN stage, because CD4 promoter-driven SPA-1 expression hardly affected T-cell development. Rap1A17, a dominant-negative Rap mutant, interfered with the generation of double-positive (DP) cells from Rag2 -/- fetal thymocytes in vitro in the presence of anti-CD3ε antibody and Notch ligand. Rap GTPases were activated in a DN cell line by the expression of self-oligomerizing CD3 (CD8:CD3ε chimera), which substituted autonomous pre-T-cell receptor (TCR) signal, inducing CD69 expression and CD25 down-regulation. Reciprocally, expression of C3G, a Rap guanine nucleotide exchange factor, in both normal and Rag2 -/- DN cells markedly enhanced Notch-dependent generation and expansion of DP cells without additional anti-CD3ε antibody, thus bypassing pre-TCR. Defective aβ T-cell development in the conditional SPA-1-transgenic mice was restored completely by introducing a p53 -/- mutation. These results suggest that endogenous Rap GTPases downstream of pre-TCR play an essential role in rescuing pre-T cells from the p53-mediated checkpoint response, thus allowing Notch-mediated expansion and differentiation.

    Original languageEnglish
    Pages (from-to)4565-4573
    Number of pages9
    JournalBlood
    Volume112
    Issue number12
    DOIs
    Publication statusPublished - Dec 1 2008

    Fingerprint

    T-cells
    T-Cell Antigen Receptor
    GTP Phosphohydrolases
    T-Lymphocytes
    Anti-Idiotypic Antibodies
    Cells
    Guanine Nucleotide Exchange Factors
    Antibodies
    Cell death
    Thymocytes
    Transgenic Mice
    Cell Death
    Down-Regulation
    Chemical activation
    Ligands
    Cell Line
    Defects
    Mutation
    Proteins

    All Science Journal Classification (ASJC) codes

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

    Cite this

    Kometani, K., Moriyama, M., Nakashima, Y., Katayama, Y., Wang, S. F., Yamasaki, S., ... Minato, N. (2008). Essential role of Rap signal in pre-TCR-mediated {beta}-selection checkpoint in {alpha}{beta} T-cell development. Blood, 112(12), 4565-4573. https://doi.org/10.1182/blood-2008-06-164517

    Essential role of Rap signal in pre-TCR-mediated {beta}-selection checkpoint in {alpha}{beta} T-cell development. / Kometani, Kohei; Moriyama, Masaki; Nakashima, Yasuhiro; Katayama, Yoshinori; Wang, Shu Fang; Yamasaki, Shou; Saito, Takashi; Hattori, Masakazu; Minato, Nagahiro.

    In: Blood, Vol. 112, No. 12, 01.12.2008, p. 4565-4573.

    Research output: Contribution to journalArticle

    Kometani, K, Moriyama, M, Nakashima, Y, Katayama, Y, Wang, SF, Yamasaki, S, Saito, T, Hattori, M & Minato, N 2008, 'Essential role of Rap signal in pre-TCR-mediated {beta}-selection checkpoint in {alpha}{beta} T-cell development', Blood, vol. 112, no. 12, pp. 4565-4573. https://doi.org/10.1182/blood-2008-06-164517
    Kometani K, Moriyama M, Nakashima Y, Katayama Y, Wang SF, Yamasaki S et al. Essential role of Rap signal in pre-TCR-mediated {beta}-selection checkpoint in {alpha}{beta} T-cell development. Blood. 2008 Dec 1;112(12):4565-4573. https://doi.org/10.1182/blood-2008-06-164517
    Kometani, Kohei ; Moriyama, Masaki ; Nakashima, Yasuhiro ; Katayama, Yoshinori ; Wang, Shu Fang ; Yamasaki, Shou ; Saito, Takashi ; Hattori, Masakazu ; Minato, Nagahiro. / Essential role of Rap signal in pre-TCR-mediated {beta}-selection checkpoint in {alpha}{beta} T-cell development. In: Blood. 2008 ; Vol. 112, No. 12. pp. 4565-4573.
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    AU - Katayama, Yoshinori

    AU - Wang, Shu Fang

    AU - Yamasaki, Shou

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