The p85β regulatory subunit of phosphoinositide 3-kinase has unique and redundant functions in B cells

Phosphoinositide kinase (PI3K) is activated by various receptors on lymphocytes and regulates development, activation, and tolerance. Genetic ablation of PI3K function in T cells leads to the appearance of autoimmune disorders. In B cells, loss of the class IA regulatory subunit p85 alpha causes a partial defect in B cell development and proliferation, whereas loss of p85 beta alone causes no apparent changes in B cell function. Here we investigate further the consequences of p85 beta deletion in B cells, in the presence or absence of p85 alpha. We demonstrate that p85 beta partially compensates for loss of p85 alpha in B cell development and peripheral survival, with greater defects observed when both isoforms are absent. BCR-mediated AKT phosphorylation is partially reduced in p85 alpha-deficient B cells and further diminished with concomitant loss of p85 beta. Unexpectedly, loss of p85 beta results in increased BCR-mediated proliferation and ERK phosphorylation. These results indicate that the p85 beta regulatory isoform has partially overlapping functions with p85 alpha in B cells as well as a unique role in opposing BCR responses.