PI3Ks in Lymphocyte Signaling and Development

Abstract

Lymphocyte development and function are regulated by tyrosine kinase and G-protein coupled receptors. Each of these classes of receptors activates PI3K. Here we summarize current understanding of how PI3K contribute to key aspects of the adaptive immune system.

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

“…B Cell Signaling-Genetic or pharmacological inactivation of p110␦ strongly blocks BCR-mediated AKT activation and proliferation (16,35). These observations support the model that p110␦ is the primary PI3K catalytic isoform engaged by BCR signalosomes.…”

“…The p110␦ isoform has important functions in T cell clonal expansion, differentiation, and trafficking (16). However, PI3K activation is not fully abrogated in p110␦-deficient T cells and some functional capacity is retained (38).…”

“…A major function of class IA PI3K in BCR signaling is to promote activation of PLC␥ to drive Ca 2ϩ mobilization (16,36). As reported previously (27), IC87114 significantly suppressed the Ca 2ϩ response of B cells stimulated with anti-IgM (Fig.…”

“…The ideal targeted therapy would enhance anti-tumor immunity while preserving patient immunity to infection. Two class I PI3K isoforms that are highly expressed in leukocytes, p110␥ and p110␦, are known to have pleiotropic functions in a variety of immune cells (1,16). For years there have been useful reagents to study p110␥ and p110␦, including selective small molecule inhibitors and mouse strains with null mutations, conditional alleles, and kinase-inactive knock-in alleles.…”

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

“…42: 3381-3393 activation of PKC family members, MAPK activation, and the release of Ca 2+ from intracellular stores, which finally leads to influx of extracellular Ca 2+ . Elevated intracellular Ca 2+ -levels induce the activity of serine/threonine-specific phosphatase calcineurin and, in turn, a set of Ca 2+ -regulated transcription factors, in particular of NFAT and NF-κB factors that control various gene expression programs [1].An important signaling cascade induced after BCR engagement encompasses the lipid kinase family of class I PI3Ks [2][3][4]. Mature peripheral B cells lacking a BCR could be rescued from apoptosis by the ectopic expression of a constitutively active catalytic subunit of PI3K, indicating that PI3K signals support the survival of resting mature B cells by "tonic" BCR signals [5].…”