The catalytic PI3K isoforms p110γ and p110δ contribute to B cell development and maintenance, transformation, and proliferation

Class I PI3K-dependent signaling regulates cell proliferation, differentiation, and survival. Analysis of gene-deficient mice revealed specific roles for the hematopoietically expressed PI3K catalytic subunits, p110 gamma and p110 delta, in development and function of T and B lymphocytes. However, the functional redundancy between these two PI3K isoforms in the B cell lineage remains unclear. Here, we demonstrate that p110 delta and p110 gamma are expressed in B cells at early developmental stages. Normal B cell differentiation requires both isoforms, as p110 gamma/p110 delta double deficiency causes an increased percentage of CD43(hi)/B220(+)/CD19(-) cells as compared with single deficiency. Interestingly, initial transformation efficiency of B cell precursors was strongly reduced in double-deficient cells following transformation by p185 bcr-abl or v-abl oncogenes as compared with single-deficient cells. The requirement of p110 gamma and p110 delta in B cell development is underlined by reduced splenic B cell numbers of p110 gamma/p110 delta double-deficient mice and of lethally irradiated wild-type mice reconstituted with double-deficient BM. Moreover, the peripheral maintenance of p110 gamma/p110 delta double-deficient T and B cells was highly impaired following adoptive transfer of double-deficient splenocytes into wildtype mice. Functionally, LPS stimulation of splenocytes revealed proliferation defects resulting in decreased survival of p110 gamma/p110 delta double-deficient B cells, which correlated with impaired induction of D-type cyclins and Bcl-X-L. Surprisingly, this was not observed when purified B cells were analyzed, indicating a contribution of likely cell-extrinsic factor(s) to the impaired proliferation of double-deficient B cells. Thus, we provide novel evidence that p110 gamma and p110 delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells. J. Leukoc. Biol. 87: 1083-1095; 2010.