The PI3K Isoforms p110a and p110d are Essential for Pre-B Cell Receptor Signaling and B Cell Development
Faruk Ramadani,1 Daniel J. Bolland,2 Fabien Garcon,1 Juliet L. Emery,1 Bart Vanhaesebroeck,3 Anne E. Corcoran,2 and Klaus Okkenhaug1*
1Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK
2Chromatin and Gene expression, The Babraham Institute, Cambridge CB22 3AT, UK
3Centre for Cell Signaling, Institute of Cancer, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
B cell development is controlled by a series of checkpoints that ensure that the immunoglobulin (Ig)-encoding genes are assembled in frame to produce a functional B cell receptor (BCR) and antibodies. The BCR consists of Ig proteins in complex with the immunoreceptor tyrosine-based activation motif (ITAM)-containing Iga and Igß chains. Whereas the activation of Src and Syk tyrosine kinases 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 p110d isoform of phosphoinositide 3-kinase (PI3K) in agonist-induced BCR signaling; however, early B cell development and mature B cell survival, which depend on tonic BCR signaling, are not substantially affected by a deficiency in p110d. Here, we show that in the absence of p110d, p110a, but not p110ß, can compensate to promote early B cell development in the bone marrow and B cell survival in the spleen. In the absence of both p110a and p110d activities, pre-BCR signaling fails to suppress the production of recombination-activating gene (Rag) protein and to promote developmental progression of B cell progenitors. By contrast, p110a does not contribute to agonist-induced BCR signaling. These studies indicate that either p110a or p110d can mediate tonic signaling from the BCR, but that only p110d can contribute to antigen-dependent activation of B cells. |
