Essential role of Rap signal in pre-TCR-mediated Β-selection checkpoint in άΒ T-cell development

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

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    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

    All Science Journal Classification (ASJC) codes

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

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  • Cite this

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