Abstract
Phosphoinositide-3 kinase (PI3K) signaling is important for the survival of numerous cell types and class IA of PI3K is specifically required for the development of B cells but not for T cell development. Here, we show that class IA PI3K-mediated signals induce the expression of the transcription factor Pax5, which plays a central role in B cell commitment and differentiation by activating the expression of central B cell-specific signaling proteins such as SLP-65 and CD19. Defective class IA PI3K function leads to reduction in Pax5 expression and prevents B cell development beyond the stage expressing the precursor B cell receptor (pre-BCR). Investigating the mechanism of PI3K-induced Pax5 expression revealed that it involves a network of transcription factors including FoxO1 and Irf4 that directly binds to the Pax5 gene. Together, our results suggest that PI3K signaling links survival and differentiation of developing B cells with B cell identity and that decreased PI3K activity in pre-B cells results in reduced Pax5 expression and lineage plasticity.
Highlights
Phosphoinositide-3 kinase (PI3K) signaling is important for the survival of numerous cell types and class IA of PI3K is required for the development of B cells but not for T cell development
We found that Pax[5] and CD19 expression was elevated in these cells (Fig. 1a and Fig. S1b and data not shown)
To test whether FoxO1 was involved in the PI3K-dependent regulation of Pax[5], we introduced a constitutively active form of FoxO1 (FoxO1-A3) or an empty control vector (EV) into cells from a bm-derived wt pre-B cell line and found that FoxO1-A3 led to reduced Pax[5] expression (Fig. 5b,c)
Summary
PI3K regulates Pax[5] expression. Analysis of mice with impaired class IA PI3K in B/T lymphocyte progenitors revealed that B cell development is selectively blocked at the pre-B cell stage[24]. To investigate the role of Irf[4] in PI3K-dependent regulation of Pax[5] expression, we confirmed that Irf[4] is induced upon treatment of SLP-65-deficient pre-B cells with the PI3K inhibitor LY294002 (Fig. 6a) or after introduction of FoxO1-A3 into a bm-derived wt pre-B cell line (Fig. 6b) In line with these findings, p110dKO pre-B cells showed elevated levels of Irf[4] transcripts (Fig. 6c). Enforced expression of Irf[4] repressed PIRE-induced luciferase expression confirming the repressive effect of Irf[4] on the fragment containing PIRE (Fig. 7f) Together, these results suggest that class IA PI3K controls B cell development by induction of Pax[5] gene expression through the activation of the Pax[5] enhancer region.
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