Phosphoinositide 3-kinase (PI3K) activation has been implicated in many cellular responses, including fibroblast growth, transformation, survival, and chemotaxis, Although PI3K is activated by several agents that stimulate T and B cells, the role of PI3K in Lymphocyte function is not clear. The mouse gene encoding the PI3K adapter subunit p85 alpha and its splice variants p55 alpha and p50 alpha was disrupted. Most p85 alpha-p55 alpha-p50 alpha(-/-) mice die within days after birth. Lymphocyte development and function was studied with the use of the RAG2-deficient blastocyst complementation system. Chimeric mice had reduced numbers of peripheral mature B cells and decreased serum immunoglobulin. The B cells that developed had diminished proliferative responses to antibody to immunoglobulin M, antibody to CD40, and Lipopolysaccharide stimulation and decreased survival after incubation with interleukin-A In contrast, T cell development and proliferation was normal. This phenotype is similar to defects observed in mice lacking the tyrosine kinase Btk.