Research ArticleImmunology

The PI3K Isoforms p110α and p110δ Are Essential for Pre–B Cell Receptor Signaling and B Cell Development

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Sci. Signal.  10 Aug 2010:
Vol. 3, Issue 134, pp. ra60
DOI: 10.1126/scisignal.2001104

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B cell development is controlled by a series of checkpoints that ensure that the immunoglobulin (Ig)–encoding genes produce a functional B cell receptor (BCR) and antibodies. As part of this process, recombination-activating gene (Rag) proteins regulate the in-frame assembly of the Ig-encoding genes. The BCR consists of Ig proteins in complex with the immunoreceptor tyrosine-based activation motif (ITAM)–containing Igα and Igβ chains. Whereas the activation of the tyrosine kinases Src and Syk is essential for BCR signaling, the pathways that act downstream of these kinases are incompletely defined. Previous work has revealed a key role for the p110δ isoform of phosphatidylinositol 3-kinase (PI3K) in agonist-induced BCR signaling; however, early B cell development and mature B cell survival, which depend on agonist-independent or “tonic” BCR signaling, are not substantially affected by a deficiency in p110δ. Here, we show that p110α, but not p110β, compensated in the absence of p110δ to promote early B cell development in the bone marrow and B cell survival in the spleen. In the absence of both p110α and p110δ activities, pre-BCR signaling failed to suppress the production of Rag proteins and to promote developmental progression of B cell progenitors. Unlike p110δ, however, p110α did not contribute to agonist-induced BCR signaling. These studies indicate that either p110α or p110δ can mediate tonic signaling from the BCR, but only p110δ can contribute to antigen-dependent activation of B cells.

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