Many receptor and nonreceptor tyrosine kinases activate phosphoinositide 3-kinases (P13Ks). To assess the role of the delta isoform of the p110 catalytic subunit of P13Ks, we derived enzyme-deficient mice. The mice are viable but have decreased numbers of mature B cells, a block in pro-B- cell differentiation, and a B1 B-cell deficiency. Both immunoglobulin M receptor-induced Ca2+ flux and proliferation in response to B-cell mitogens are attenuated. Immunoglobulin levels are decreased substantially . The ability to respond to T-cell-independent antigens is markedly reduced, and the ability to respond to T-cell- dependent antigens is completely eliminated. Germinal center formation in the spleen in response to antigen stimulation is disrupted. These results define a nonredundant signaling pathway(s) utilizing the delta isoform of p110 P13K for the development and function of B cells
