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, p110γ and p110δ, 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 p110δ and p110γ are expressed in B cells at early developmental stages. Normal B cell differentiation requires both isoforms, as p110γ/p110δ double deficiency causes an increased percentage of CD43hi/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 p110γ and p110δ in B cell development is underlined by reduced splenic B cell numbers of p110γ/p110δ double‐deficient mice and of lethally irradiated wild‐type mice reconstituted with double‐deficient BM. Moreover, the peripheral maintenance of p110γ/p110δ double‐deficient T and B cells was highly impaired following adoptive transfer of double‐deficient splenocytes into wild‐type mice. Functionally, LPS stimulation of splenocytes revealed proliferation defects resulting in decreased survival of p110γ/p110δ double‐deficient B cells, which correlated with impaired induction of D‐type cyclins and Bcl‐XL. 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 p110γ and p110δ have overlapping and cell‐extrinsic roles in the development, peripheral maintenance, and function of B cells.