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The Effect of Deleting p110 on the Phenotype and Function of PTEN-Deficient B Cells¹

Michelle L. Janas^1,*, Daniel Hodson^*, Zania Stamataki^2,*, Sue Hill^3,*, Katie Welch^*, Laure Gambardella^*, Lloyd C. Trotman, Pier Paolo Pandolfi, Elena Vigorito^* and Martin Turner^4,*

^* Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham, Cambridge, United Kingdom; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; and Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02115

Control of the intracellular levels of phosphatidylinositol-(3, 4, 5)-trisphosphate by PI3K and phosphatase and tensin homolog (PTEN) is essential for B cell development and differentiation. Deletion of the PI3K catalytic subunit p110 leads to a severe reduction in B1 and marginal zone (MZ) B cells, whereas deletion of PTEN results in their expansion. We have examined the relationship between these two molecules by generating mice with a B cell-specific deletion of PTEN (PTEN^B) and a concurrent germline deletion of p110. The expanded B1 cell population of PTEN^B mice was reduced to normal levels in PTEN^B/p110 mutant mice, indicating a critical role for the p110 isoform in the expansion of B1 cells. However, numbers of MZ B cells in the PTEN^B/p110 mutants was intermediate between wild-type and PTEN^B-deficient mice, suggesting an additional role for other PI3K catalytic isoforms in MZ differentiation. Furthermore, the defective class switch recombination in PTEN^B B cells was only partially reversed in PTEN^B/p110 double mutant B cells. These results demonstrate an epistatic relationship between p110 and PTEN. In addition, they also suggest that additional PI3K catalytic subunits contribute to B cell development and function.

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 Leukaemia Research Fund, the Medical Research Council, the Biotechnology and Biological Sciences Research Council, and Cancer Research United Kingdom.

² Current address: Division of Immunity and Infection, University of Birmingham Medical School, Birmingham, U.K.

³ Current address: ImmunoBiology Limited, Babraham Research Campus, Babraham, Cambridge, U.K.

⁴ Address correspondence and reprint requests to Dr. Martin Turner, Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham, Cambridge CB22 3AT, U.K. E-mail address: martin.turner{at}bbsrc.ac.uk

⁵ Abbreviations used in this paper: PIP₂, phosphatidylinositol-(4, 5)-bisphosphate; PIP₃, phosphatidylinositol-(3, 4, 5)-trisphosphate; PTEN, phosphatase and tensin homolog; PTEN^B, B cell-specific deletion of PTEN; PDK1, phosphoinositide-dependent protein kinase-1; PKB, protein kinase B; MZ, marginal zone; WT, wild type; AID, activation-induced cytidine deaminase; FO, follicular; CSR, class switch recombination; BAFF, B cell activating factor of the TNF family.