Proliferation and Survival of Activated B Cells Requires Sustained Antigen Receptor Engagement and Phosphoinositide 3-Kinase Activation

Abstract

In this study, we investigate the extracellular and intracellular signals that drive cell cycle progression of activated B cells in the absence of T cell help. We find that brief engagement of the B cell receptor is sufficient to induce a single cell division in a fraction of cells, but that survival during successive cell divisions requires sustained receptor stimulation. In contrast, T cells have been shown previously to commit to multiple cell divisions following brief TCR engagement. Both early and late B cell receptor signals are blocked by inhibitors of phosphoinositide 3-kinase and mammalian target of rapamycin and are associated with S6 kinase activation and increased cell size. The requirement for ongoing Ag receptor signaling can be overcome by engagement of CD40 but only partially by IL-4. Proliferation driven by LPS also requires sustained exposure to the stimulus. These findings reveal checkpoints that may limit T-independent B cell responses when Ag exposure is transient.

Analysis of the Major Patterns of B Cell Gene Expression Changes in Response to Short-Term Stimulation with 33 Single Ligands

“…It is possible that different gene response patterns to anti-Ig in the B cell subsets could dilute or cancel each other out at the population level, contributing to less up-regulation of Ccnd2 and Plk. This explanation also fits with the observation that mouse splenic B cells showed more death in response to anti-Ig than to CD40L or LPS (43)(44)(45). Another gene that was strongly induced by CD40L, CpG, IL-4, and LPS, but not by anti-Ig, is myristoylated alaninerich protein kinase C substrate (MARCKS).…”

B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton’s Tyrosine Kinase

“…This study demonstrated that sustained BCR signaling through PI3K is required for proliferation and survival of B cells. LY294002 and CsA were effective at blocking the activation of B cells at late time points in which Akt activation was weak and not PI3K dependent (19). This suggests that newly generated FOXO1 protein may be inefficiently phosphorylated by Akt and degraded at late times post-BCR stimulation, necessitating the newly described PI3K/Btk/calcineurin-dependent mechanism for inhibiting further expression of FOXO1 mRNA.…”

“…As a result, the cells enter and progress through the cell cycle, receiving a variety of survival signals. Each of these processes depends on PI3K (19). A major downstream target of PI3K signaling in BCR-stimulated B cells is Akt (20).…”

The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease

“…33,34 Similarly, sustained activation of the PI3K/Akt pathway is required to drive cell cycle progression in activated T-and B-cells. 35,36 Therefore, to further investigate whether insufficient activation of these kinases is responsible for the lower proliferative capacity of the prognostically favorable CLL B-cell subset, we introduced cDNA constructs encoding for constitutively active MEK2 and constitutively active Akt in primary CLL B-cells that were nonresponsive to CpG ODN-induced proliferation. Although both constructs were efficiently transfected, induction of cyclin A following CpG ODN stimulation was observed only in CLL B-cells transfected with constitutively active Akt, whereas cyclin A was not induced in cells with enforced activation of ERK.…”

“…[33][34][35][36] Although a role for JNK in B-cell proliferation has also been established, it is still not known whether quantitative differences in JNK activation can influence cell cycle progression. [37][38][39] We therefore decided to further investigate the possibility that the stronger proliferative response of progressive/V H unmutated CLL B-cells is due to increased signaling through the Akt or ERK pathway.…”