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

Abstract

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, p110gamma and p110delta, 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 p110delta and p110gamma are expressed in B cells at early developmental stages. Normal B cell differentiation requires both isoforms, as p110gamma/p110delta 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 p110gamma and p110delta in B cell development is underlined by reduced splenic B cell numbers of p110gamma/p110delta double-deficient mice and of lethally irradiated wild-type mice reconstituted with double-deficient BM. Moreover, the peripheral maintenance of p110gamma/p110delta 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 p110gamma/p110delta 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 p110gamma and p110delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells.

PI3K signaling in arterial diseases: Non redundant functions of the PI3K isoforms

“…These accumulating data indicate that PI3Kd appears to be the main isoform involved in the regulation of B cell functions, including their maturation and activation. However, Beer-Hammer et al revealed that the absence of p110g and p110d impaired B cell maturation to a significantly higher extent than the loss of p110d alone (Beer-Hammer et al, 2010). Likewise, p110g/p110d double-deficient splenocytes presented a proliferation defect following LPS stimulation, resulting in a decrease in survival.…”

The Selective Phosphoinoside-3-Kinase p110δ Inhibitor IPI-3063 Potently Suppresses B Cell Survival, Proliferation, and Differentiation

“…In T cells, p110γ plays a role in early development and is important for trafficking of activated effector cells (14, 15). One study reported that mice lacking both p110δ and p110γ had greater defects in B cell survival and proliferation compared to p110δ knockout alone (16). The effects of chemical p110γ inhibition on B cell function have not been reported.…”

PI3-Kinase-γ Has a Distinct and Essential Role in Lung-Specific Dendritic Cell Development

“…The p110g subunit has been suggested to play a prominent role in immunity and inflammation, in particular by regulating migration of multiple cell types such as neutrophils and macrophages to the site of inflammation (Hirsch et al, 2000;Li et al, 2000). Furthermore, it has been found to have a minor role in lymphocyte development (Beer-Hammer et al, 2010;Sasaki et al, 2000), as well as T cell proliferation (Ladygina et al, 2013). Moreover, p110g is implicated in multiple human diseases such as atherosclerosis (Zotes et al, 2013) and is thus seen as a promising therapeutic target in many inflammatory disorders (Costa et al, 2011).…”