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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.

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IMMUNOBIOLOGY

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

Kohei Kometani1,*, Masaki Moriyama1,*, Yasuhiro Nakashima2,*, Yoshinori Katayama2, Shu-Fang Wang1, Sho Yamasaki3, Takashi Saito3, Masakazu Hattori2, and Nagahiro Minato1,2

1 Department of Immunology and Cell Biology, Graduate School of Biostudies and 2 Graduate School of Medicine, Kyoto University, Kyoto; and 3 Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

We demonstrate that lck promoter–driven conditional expression of transgenic SPA-1, a Rap GTPase-activation protein, causes a profound defect of {alpha}β T-cell development at the CD4/CD8 double-negative (DN) stage due to enhanced cell death without affecting {gamma}{delta} 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{epsilon} antibody and Notch ligand. Rap GTPases were activated in a DN cell line by the expression of self-oligomerizing CD3 (CD8:CD3{epsilon} 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-CD3{epsilon} antibody, thus bypassing pre-TCR. Defective {alpha}β 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.


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