HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shiroki, F. Articles by Koyasu, S. Search for Related Content PubMed PubMed Citation Articles by Shiroki, F. Articles by Koyasu, S.

The p85 Regulatory Subunit of Class IA Phosphoinositide 3-Kinase Regulates -Selection in Thymocyte Development¹

Fumiko Shiroki^*, Satoshi Matsuda^*,, Tomomitsu Doi^*,, Mari Fujiwara^*,, Yoshito Mochizuki^*, Takashi Kadowaki^,, Harumi Suzuki^*, and Shigeo Koyasu^2,*,

^* Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan; Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and Department of Pathology, Research Institute, International Medical Center of Japan, Tokyo, Japan

We examined the role of class IA PI3K in pre-TCR controlled -selection and TCR-controlled positive/negative selection in thymic development. Using mice deficient for p85, a major regulatory subunit of the class IA PI3K family, the role of class IA PI3K in -selection was examined by injection of anti-CD3 mAb into p85^–/–Rag-2^–/– mice, which mimics pre-TCR signals. Transition of CD4^–CD8^– double-negative (DN) to CD4⁺CD8⁺ double-positive (DP) thymocytes triggered by anti-CD3 mAb was significantly impaired in p85^–/–Rag-2^–/– compared with p85^+/–Rag-2^–/– mice. Furthermore, DP cell numbers were lower in p85^–/–DO11.10/Rag-2^–/– TCR-transgenic mice than in DO11.10/Rag-2^–/– mice. In addition, inhibition by IC87114 of the major class IA PI3K catalytic subunit expressed in lymphocytes, p110, blocked transition of DN to DP cells in embryonic day 14.5 fetal thymic organ culture without affecting cell viability. In the absence of phosphatase and tensin homolog deleted on chromosome 10, where class IA PI3K signals would be amplified, the DN to DP transition was accelerated. In contrast, neither positive nor negative selection in Rag-2^–/–TCR-transgenic mice was perturbed by the lack of p85. These findings establish an important function of class IA PI3K in the pre-TCR-controlled developmental transition of DN to DP thymocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Mitsubishi Foundation, a Keio University Special Grant-in-Aid for Innovative Collaborative Research Project, a Grant-in-Aid for Scientific Research for Young Scientist (16790293 to S.M.) from the Japan Society for the Promotion of Science, a Grant-in-Aid for Scientific Research on Priority Areas (14021110 to S.K. and 16043248 to S.M.), a National Grant-in-Aid for the Establishment of a High-Tech Research Center in a private university, and a Scientific Frontier Research Grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

² Address correspondence and reprint requests to Dr. Shigeo Koyasu, Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail address: koyasu{at}sc.itc.keio.ac.jp

³ Abbreviations used in this paper: DN, double negative; DP, double positive; SP, single positive; tg, transgenic; PI, phosphatidylinositol; Pten, phosphatase and tensin homolog deleted on chromosome 10; PDK, phosphoinositide-dependent kinase; 7AAD, 7-aminoactinomycin D; FTOC, fetal thymic organ culture.