Emergence of the PI3-kinase pathway as a central modulator of normal and aberrant B cell differentiation

Abstract

Phosphoinositide 3-kinase (PI3K) defines a family of lipid kinases that direct a wide range of cellular processes and cell fate decisions. Since its discovery, and that of its enzymatic antagonist PTEN, much of the focus on PI3K has been on its oncogenic potential. In recent years, studies on PI3K signaling in B lymphocytes have established the importance of this pathway in effecting B cell differentiation and associated molecular events such as V(D)J recombination and class switch recombination. Intriguing new findings also indicate that there is specificity in the PI3K pathway in B cells, including preferential expression or usage of particular PI3K isoforms and counter-regulation by the PTEN and SHIP phosphatases. The role of PI3K adaptor proteins (CD19, BCAP, and TC21) has also undergone revision to reflect both shared and unique properties. The emergence of Foxo1 as a critical PI3K regulatory target for B cell differentiation has united membrane proximal regulatory events orchestrated by PI3K/PTEN/SHIP with key transcriptional targets. Insights into the regulation and impact of PI3K signaling have been brought to bear in new treatments for B cell malignancies, and will also be an important topic of consideration for B cell-dependent autoimmune diseases.

Figure 1. PI3K signaling pathway in B cell development

Pro-B cell development is supported by IL-7 stimulation via the PI3K and STAT5 pathways. Weak PI3K signaling promotes retention of Foxo1 in the nucleus to drive Il7ra expression. PI3K signaling via the pre-BCR can be augmented by CD19 and countered by BLNK(SLP-65). Expression of pre-BCR components is repressed in an IRF4/IRF8-dependent manner to permit Foxo1-dependent expression of Rag in resting pre-B cells. Peripheral B cells require PI3K signaling to promote survival while Foxo1 activity is crucial for expression of Sell and Aicda, suggesting a dynamic balance for Foxo1 activity in peripheral B cell homeostasis and differentiation.