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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4565-4573. Prepublished online as a Blood First Edition Paper on September 18, 2008; DOI 10.1182/blood-2008-06-164517. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-06-164517v1 112/12/4565    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kometani, K. Articles by Minato, N. Search for Related Content PubMed PubMed Citation Articles by Kometani, K. Articles by Minato, N. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 20, 2008 Accepted August 26, 2008 Essential role of Rap signal in pre-TCR-mediated -selection checkpoint in T cell development Kohei Kometani, Masaki Moriyama, Yasuhiro Nakashima, Yoshinori Katayama, Shu-Fang Wang, Sho Yamasaki, Takashi Saito, Masakazu Hattori, and Nagahiro Minato* Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Laboratory for Cell Signalling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan * Corresponding author; email: minato{at}imm.med.kyoto-u.ac.jp. We demonstrate that lck promoter-driven conditional expression of transgenic SPA-1, a Rap GTPase-activation protein, causes a profound defect of T cell development at the CD4/CD8 double-negative (DN) stage due to enhanced cell death without affecting 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-CD3 antibody and Notch ligand. Rap GTPases were activated in a DN cell line by the expression of self-oligomerizing CD3 (CD8:CD3 chimera), which substituted autonomous pre-T-cell receptor (TCR) signal, inducing CD69 expression and CD25 downregulation. 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-CD3 antibody, thus bypassing pre-TCR. Defective 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Katayama, M. Sekai, M. Hattori, I. Miyoshi, Y. Hamazaki, and N. Minato Rap signaling is crucial for the competence of IL-7 response and the development of B-lineage cells Blood, August 27, 2009; 114(9): 1768 - 1775. [Abstract] [Full Text] [PDF]

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