Pten is a tumor suppressor gene mutated in human cancers. We used the Cre-loxP system to generate a B cell–specific mutation of Pten in mice (bPtenflox/floxmice). bPtenflox/flox mice showed elevated numbers of B1a cells and increased serum autoantibodies. Among B2 cells in bPtenflox/flox spleens, numbers of marginal zone B (MZB) cells were significantly increased while those of follicular B (FOB) cells were correspondingly decreased. Pten-deficient B cells hyperproliferated, were resistant to apoptotic stimuli, and showed enhanced migration. The survival kinase PKB/Akt was highly activated in Pten-deficient splenic B cells. In addition, immunoglobulin class switch recombination was defective and induction of activation-induced cytidine deaminase (AID) was impaired. Thus, Pten plays a role in developmental fate determination of B cells and is an indispensable regulator of B cell homeostasis.
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3 March 2003
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March 03 2003
Critical Roles of Pten in B Cell Homeostasis and Immunoglobulin Class Switch Recombination
Akira Suzuki,
Akira Suzuki
1Department of Molecular Cell Biology, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
3Department of Biochemistry, Akita University School of Medicine, Akita 010-8543, Japan
8Advanced Medical Discovery Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada
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Tsuneyasu Kaisho,
Tsuneyasu Kaisho
2Department of Host Defense, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
4RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan
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Minako Ohishi,
Minako Ohishi
1Department of Molecular Cell Biology, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
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Manae Tsukio-Yamaguchi,
Manae Tsukio-Yamaguchi
1Department of Molecular Cell Biology, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
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Takeshi Tsubata,
Takeshi Tsubata
5Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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Pandelakis A. Koni,
Pandelakis A. Koni
7Molecular Immunology Program, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912
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Takehiko Sasaki,
Takehiko Sasaki
6Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan
8Advanced Medical Discovery Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada
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Tak Wah Mak,
Tak Wah Mak
8Advanced Medical Discovery Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada
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Toru Nakano
Toru Nakano
1Department of Molecular Cell Biology, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
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Akira Suzuki
1Department of Molecular Cell Biology, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
3Department of Biochemistry, Akita University School of Medicine, Akita 010-8543, Japan
8Advanced Medical Discovery Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada
Tsuneyasu Kaisho
2Department of Host Defense, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
4RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan
Minako Ohishi
1Department of Molecular Cell Biology, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
Manae Tsukio-Yamaguchi
1Department of Molecular Cell Biology, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
Takeshi Tsubata
5Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Pandelakis A. Koni
7Molecular Immunology Program, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912
Takehiko Sasaki
6Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan
8Advanced Medical Discovery Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada
Tak Wah Mak
8Advanced Medical Discovery Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada
Toru Nakano
1Department of Molecular Cell Biology, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
Address correspondence to Tak Wah Mak, Advanced Medical Discovery Institute, 620 University Ave., Toronto, Ontario M5G 2C1, Canada. Phone: 416-204-5302; Fax: 416-204-5300; E-mail: [email protected]
T. Kaisho, M. Ohishi, and M. Tsukio-Yamaguchi contributed equally to this work.
A. Suzuki's present address is Department of Biochemistry, Akita University School of Medicine, Akita 010-8543, Japan.
*
Abbreviations used in this paper: BM, bone marrow; CSR, class switch recombination; DC, digestion-circulation; FOB, follicular B; MEF, mouse embryonic fibroblast; MLN, mesenteric lymph node; MZB, marginal zone B; PEC, peritoneal cavity; PIP3, phosphatidyl inositol-3,4,5-triphosphate; SDF, stromal cell–derived factor; TD, thymus-dependent; TI, thymus-independent antigen.
Received:
July 01 2002
Revision Received:
January 07 2003
Accepted:
January 22 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 197 (5): 657–667.
Article history
Received:
July 01 2002
Revision Received:
January 07 2003
Accepted:
January 22 2003
Citation
Akira Suzuki, Tsuneyasu Kaisho, Minako Ohishi, Manae Tsukio-Yamaguchi, Takeshi Tsubata, Pandelakis A. Koni, Takehiko Sasaki, Tak Wah Mak, Toru Nakano; Critical Roles of Pten in B Cell Homeostasis and Immunoglobulin Class Switch Recombination . J Exp Med 3 March 2003; 197 (5): 657–667. doi: https://doi.org/10.1084/jem.20021101
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