Functional roles of PI3 Kinase in immune system

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Mice deficient for p85α regulatory subunit of PI3-kinase showed impaired B cell development and activation, and their phenotype was nearly identical to that of Btk-/- mice. Since phosphatidylinositol-(3,4,5) triphosphate, a major product of PI3-kinases has been proposed to play a critical role in membrane recruitment and activation of Btk, phenotypic resemblance of these two knockout mice seemed to reveal direct functional association between PI3-K and Btk. However, BCR-induced activation of Btk in mouse B cells was unaffected by PI3K inhibitors or by the lack of phosphoinositide-3 kinase (PI3K). Consistent with this observation, PI3K/Btk double deficient mice show more severe defects than either single knockout mouse. Activation of NF-kB and induction of Bcl-x_L and cyclin D2 were severely blocked in both PI3K^<-/-> and Btk^<-/-> single deficient B cells and transgenic expression of Bcl-x_L restored the development and BCR-induced proliferation of B cells in PI3K^<-/-> mice. Our results collectively indicate that PI3K and Btk have unique roles in proximal BCR signaling, and they have a common target further downstream in the activation of NF-kB.