The Journal of Experimental Medicine
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Published 3 March 2003. doi:10.1084/jem.20021101
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© Rockefeller University Press, 0022-1007/2003/3/657 $5.00
The Journal of Experimental Medicine, Volume 197, Number 5, 657-667

Critical Roles of Pten in B Cell Homeostasis and Immunoglobulin Class Switch Recombination

Akira Suzuki1,3,8, Tsuneyasu Kaisho2,4, Minako Ohishi1, Manae Tsukio-Yamaguchi1, Takeshi Tsubata5, Pandelakis A. Koni7, Takehiko Sasaki6,8, Tak Wah Mak8 and Toru Nakano1

1 Department of Molecular Cell Biology, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
2 Department of Host Defense, Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan
3 Department of Biochemistry, Akita University School of Medicine, Akita 010-8543, Japan
4 RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan
5 Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
6 Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan
7 Molecular Immunology Program, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912
8 Advanced Medical Discovery Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada

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: tmak{at}uhnres.utoronto.ca

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.

Key Words: PTEN • mutation • marginal zone B cells • class switch recombination • activation-induced cytidine deaminase


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