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A Crucial Role for the p110 Subunit of Phosphatidylinositol 3-Kinase in B Cell Development and Activation

Elizabeth Clayton¹, Giuseppe Bardi¹, Sarah E. Bell¹, David Chantry², C. Peter Downes³, Alexander Gray³, Lisa A. Humphries⁴, David Rawlings^5,6, Helen Reynolds¹, Elena Vigorito¹ and Martin Turner⁵

¹ Laboratory of Lymphocyte Signaling and Development, Molecular Immunology Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, United Kingdom
² COS Corporation, Bothell, WA 98021
³ Department of Biochemistry, University of Dundee, Dundee, DD1 5EH, United Kingdom
⁴ The Molecular Biology Institute, University of California, Los Angeles, CA 90095
⁵ Department of Immunology, University of Washington, School of Medicine, Seattle, WA 98195
⁶ Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA 98195

Address correspondence to M. Turner, Lymphocyte Signaling & Development Laboratory, Molecular Immunology Programme, Cambridge CB2 4AT, UK. Phone: 44-0-1223-496-460; Fax: 44-0-1223-496-023; E-mail: martin.turner{at}bbsrc.ac.uk

Mice lacking the p110 catalytic subunit of phosphatidylinositol 3-kinase have reduced numbers of B1 and marginal zone B cells, reduced levels of serum immunoglobulins, respond poorly to immunization with type II thymus-independent antigen, and are defective in their primary and secondary responses to thymus-dependent antigen. p110^-/- B cells proliferate poorly in response to B cell receptor (BCR) or CD40 signals in vitro, fail to activate protein kinase B, and are prone to apoptosis. p110 function is required for BCR-mediated calcium flux, activation of phosphlipaseC2, and Bruton's tyrosine kinase. Thus, p110 plays a critical role in B cell homeostasis and function.

Key Words: Akt • Btk • calcium • gene targeting • p110

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