PI3K signaling controls cell fate at many points in B lymphocyte development and activation

Donahue, Amber C.; Fruman, David A.

doi:10.1016/j.semcdb.2003.12.024

Cited by 59 publications

(69 citation statements)

References 130 publications

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“…Although receptor-proximal signaling events in B cells differ among TLRs and CD40, these receptors share common downstream signaling pathways such as the PI-3K, MAPK, and NF-κB pathways (21,22). This is supported by the similarity of gene expression profiles of primary B cells stimulated with distinct mitogenic agonists (23).…”

Section: Inactivation Of Glycogen Synthase Kinase 3β Is Necessary Formentioning

confidence: 93%

The B-cell antigen receptor integrates adaptive and innate immune signals

Otipoby

Waisman

Derudder

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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B cells respond to antigens by engagement of their B-cell antigen receptor (BCR) and of coreceptors through which signals from helper T cells or pathogen-associated molecular patterns are delivered. We show that the proliferative response of B cells to the latter stimuli is controlled by BCR-dependent activation of phosphoinositidyl 3-kinase (PI-3K) signaling. Glycogen synthase kinase 3β and Foxo1 are two PI-3K-regulated targets that play important roles, but to different extents, depending on the specific mitogen. These results suggest a model for integrating signals from the innate and the adaptive immune systems in the control of the B-cell immune response.BCR | B-cell proliferation | PI-3K | GSK3β | Foxo1

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Section: Inactivation Of Glycogen Synthase Kinase 3β Is Necessary Formentioning

confidence: 93%

The B-cell antigen receptor integrates adaptive and innate immune signals

Otipoby

Waisman

Derudder

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…After immunization with NP-OVA, serawere collected at 1-wk intervals, and levels of Ab binding to OVA, NP 3 -BSA or NP 20 -BSA were determined. In WT C57BL/6 mice, high-affinity NP 3 -binding Abs appeared only at later time points after immunization, resulting in an increasing ratio of NP 3 -binding/NP 20 (Fig. 2).…”

Section: Bam32 Deficiency Leads To Premature Dissolution Of Gcsmentioning

confidence: 98%

“…At the indicated days, sera were collected for measurement of low and high affinity NP-specific IgG1 (A) and IgG2a (B) Abs. Lowaffinity NP-specific Abs were detected using NP 20 -BSA-coated plates, whereas high-affinity Abs were detected using NP 3 -BSA-coated plates. The ratio of NP impairment in GC responses is due to a B cell-intrinsic function of Bam32, purified Bam32-deficient or control B cells were adoptively transferred to B cell-deficient hosts.…”

Section: Bam32 Deficiency Leads To Premature Dissolution Of Gcsmentioning

confidence: 99%

“…PI3K enzymes are strongly activated by BCR ligation (18,19), and the importance of PI3K signaling in B cell development and activation is well established (20,21). Bam32 binds PI3K lipid products, PI(3,4)P 2 and PI(3,4,5)P 3 , in vitro (15) and is recruited to the plasma membrane in a PI3K-dependent manner upon BCR ligation (14).…”

mentioning

confidence: 99%

“…Bam32-deficient B cells develop normally, but show markedly impaired BCR-triggered proliferation in vitro; however, proliferation could be fully recovered with addition of anti-CD40 and/or IL-4 stimuli (23,26). PI3K-deficient mouse models, as well as CD19 mutants lacking the ability to activate PI3K, show defective GC responses (20,27,28). In contrast, Bam32-deficient mice were reported to generate normal size GCs after immunization with SRBCs (23,26).…”

mentioning

confidence: 99%

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The Pleckstrin Homology Domain Adaptor Protein Bam32/DAPP1 Is Required for Germinal Center Progression

Zhang

Al‐Alwan²,

Marshall

2009

The Journal of Immunology

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Ab affinity maturation within germinal centers (GCs) requires weeks to complete. Several signaling pathways in B cells have been shown to be required for initiation of the GC response; however, the signaling checkpoints controlling progression and eventual dissolution of the GC reaction are poorly understood. The adaptor protein Bam32/DAPP1 was originally isolated from human GCs and functions downstream of phosphoinositide 3-kinase enzymes, which are known to have critical roles in B cell activation and GC responses. In this study we identify a unique role of Bam32/DAPP1 in promoting GC progression. Bam32-deficient mice show normal GC initiation, but premature GC dissolution after immunization with protein Ag in alum or low doses of sheep red blood cells. Adoptive transfer studies confirmed that Bam32-deficient B cells have an intrinsic impairment in the ability to mount sustained GC responses. Bam32 deficiency was also associated with impaired Ab affinity maturation. Proliferation of Bam32-deficient GC B cells was not compromised; however, these cells show impaired switch to IgG1 and increased apoptosis in situ. GCs formed by Bam32-deficient B cells contain fewer T cells, indicating that Bam32 is required for B cell–dependent T cell accumulation within established GCs. Exogenous CD40 ligand restored GC B cell numbers and switch to IgG1, indicating that Bam32-deficient B cells are competent to respond to CD40 stimulation when ligand is available. These data demonstrate that Bam32 is not required for GC initiation, but rather functions in a late checkpoint of GC progression associated with T cell recruitment and GC B cell survival.

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Evaluation of B‐cell intracellular signaling by monitoring the PI3K‐Akt axis in patients with common variable immunodeficiency and activated phosphoinositide 3‐kinase delta syndrome

Molina

Canizales

Rodríguez-Pena

et al. 2020

Cytometry Part B Clinical

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Background: Primary antibody deficiencies (PADs) are characterized by hypogammaglobulinemia and impaired B-cell differentiation. Patients with common variable immunodeficiency (CVID) present severe reductions in at least 2 serum immunoglobulins and impaired terminal differentiation of B cells. Most patients with CVID do not appear to present monogenic defects. Activated phosphoinositide 3-kinase delta syndrome (APDS), caused by gain-of-function mutations in the PIK3CD gene (p110δ), can present in patients with a CVID-like phenotype. Memory B-cell differentiation requires the orchestrated activation of numerous intracellular signaling pathways, which promote transcriptional programs required for long-term B-cell survival. The aim of this study was to develop a flow cytometry assay to trace the PI3K-Akt-mTOR pathway, a critical component of B-cell homeostasis, and analyze its status in PADs. Methods: We analyzed the intracellular expression of Akt and S6 by flow cytometry and their phosphorylation status in both baseline conditions and upon B-cell receptor activation with anti-IgM in various primary B-cell subsets of patients with CVID and APDS. Results: B cells from CVID patients showed reduced phosphorylation in Akt and S6 proteins after anti-IgM stimulation. Constitutive high baseline B-cell levels of Akt and S6 phosphorylation in a patient with APDS were reduced once m-TOR inhibition therapy was initiated.Conclusions: Intracellular flow cytometry can be routinely employed to explore alterations in the PI3K-Akt-mTOR pathway in B cells from patients with PADs. AKT and S6 phosphorylation levels are informative biomarkers that could be employed as mTOR inhibitors for monitoring therapies targeting this pathway.

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PI3K signaling controls cell fate at many points in B lymphocyte development and activation

Cited by 59 publications

References 130 publications

The B-cell antigen receptor integrates adaptive and innate immune signals

The B-cell antigen receptor integrates adaptive and innate immune signals

The Pleckstrin Homology Domain Adaptor Protein Bam32/DAPP1 Is Required for Germinal Center Progression

Evaluation of B‐cell intracellular signaling by monitoring the PI3K‐Akt axis in patients with common variable immunodeficiency and activated phosphoinositide 3‐kinase delta syndrome

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