A Crucial Role for the p110δ Subunit of Phosphatidylinositol 3-Kinase in B Cell Development and Activation

Clayton, Elizabeth; Bardi, Giuseppe; Bell, Sarah E.; Chantry, David; Downes, C P; Gray, Alexander; Humphries, Lisa A.; Rawlings, David J.; Reynolds, Helen; Vigorito, Elena; Turner, Martin

doi:10.1084/jem.20020805

Cited by 418 publications

(431 citation statements)

References 61 publications

Supporting

Mentioning

408

Contrasting

Order By: Relevance

“…Similar results were observed using LY294002 inhibitor (data not shown). Because the PI3K catalytic subunit p110␦ contributes a significant proportion of PI3K signaling in B cells (31)(32)(33), we examined the role of this isoform, using the p110␦-selective inhibitor IC (37,38) and B cells from mice carrying an inactivating mutation of p110␦ (33). Pretreatment of normal B cells with IC partially inhibited their ability to induce IL-2 production in a dose-dependent fashion (Fig.…”

Section: The P110␦ Signaling Is Required For Bcr-mediated Ag Presentamentioning

confidence: 99%

See 1 more Smart Citation

Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation

Al‐Alwan

Okkenhaug

Vanhaesebroeck

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

The BCR serves to both signal cellular activation and enhance uptake and presentation of Ags by B cells; however, the intracellular signaling mechanisms linking the BCR to Ag presentation functions have been controversial. PI3Ks are critical signaling enzymes controlling many cellular processes, with the p110δ isoform playing a critical role in BCR signaling. In this study, we used pharmacological and genetic approaches to evaluate the role of p110δ signaling in Ag presentation by primary B lymphocytes. It was found that activation of allogeneic T cells is significantly reduced when B cells are pretreated with global PI3K inhibitors, but was intact when p110δ signaling was specifically inactivated. In contrast, inactivation of p110δ significantly impaired the ability of B cells to activate T cells in a BCR-mediated Ag uptake and presentation model. Prestimulation of p110δ-inactivated B cells with anti-CD40 or LPS could not rescue their BCR-mediated Ag presentation ability to normal levels. p110δ signaling was required for efficient presentation of either anti-Ig or protein Ag via a lysozyme-specific BCR. p110δ-inactivated B cells were able to internalize Ag normally, and no defects in association of Ag with lysosome-associated membrane protein 1+ late endosomes were observed; however, these cells were less effective in forming polarized conjugates with Ag-specific T cells. Our data demonstrate a role for p110δ signaling in B cell Ag presentation function, implicating 3-phosphoinositides and their targets in the latter stages of this process.

show abstract

Section: The P110␦ Signaling Is Required For Bcr-mediated Ag Presentamentioning

confidence: 99%

“…30). The expression of the p110␦ isoform is restricted to immune cells and has been shown to play critical roles in B cell activation (31)(32)(33). In this study, we have investigated whether p110␦ plays a role in Ag presentation function of primary B cells using both genetic inactivation of p110␦ and a p110␦-specific inhibitor IC87114 (IC).…”

mentioning

confidence: 99%

Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation

Al‐Alwan

Okkenhaug

Vanhaesebroeck

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Tissue sections were doubled-stained for IgD (Binding Site) in combination with IgM (Serotec), CD3 (KT3; Serotec) or CD4 (GK1.5; Serotec), or for MOMA-1 (Serotec) in combination with IgM (R6-60.2; BD BioSciences) [42,43].…”

Section: Immunohistologymentioning

confidence: 99%

Impaired B‐1 and B‐2 B cell development and atypical splenic B cell structures in IL‐7 receptor‐deficient mice

et al. 2004

View full text Add to dashboard Cite

The cytokine IL-7 and its receptor are essential for normal B and T lymphopoiesis. We have analyzed the role of this receptor in B cell development throughout ontogeny in IL-7 receptor a-deficient mice. We demonstrate that the IL-7 receptor becomes progressively more important with age. B lymphopoiesis takes place, albeit at reduced levels, in fetal liver and bone marrow of young mice, but is arrested in adults. The outcome is a severe reduction, from an early age, in peripheral B cells including follicular, marginal zone and B-1 B cells as well as perturbed splenic B cell structures, which are restored after adoptive transfer of normal spleen cells. We conclude that in the absence of the IL-7 receptor, the residual B lymphopoiesis occurring early in ontogeny must be facilitated by another component, whereas the IL-7 receptor is the key factor in adults. The impairment of marginal zone and B-1 B cells in IL-7 receptor-but not IL-7-deficient mice suggests non-redundant functions for the IL-7 receptor ligands, IL-7 and thymic stromal lymphopoietin.

show abstract

“…Our previous study found that T cells from p110d-D910A mice had reduced antigen-induced proliferation in vitro, but this appears in some cases to be overcome by strong signaling through costimulatory receptors [11]. In contrast, p110d-deficient B cells have major defects in activation by multiple stimuli in vitro, and blunted antibody responses in vivo [11][12][13]. Thus, while PI3K isoforms likely play distinct roles in B cells, T cells and neutrophils, their respective roles in regulating systemic cytokine production patterns, cell-mediated immunity and host defense functions remain unexplored.…”

mentioning

confidence: 99%

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

et al. 2007

View full text Add to dashboard Cite

Phosphoinositide 3-kinases (PI3K) regulate immune activation via their roles in signal transduction of multiple classes of receptors. Here, we examined the effect of genetic inactivation of the hemopoietic cell-restricted PI3K isoform p110d on systemic cytokine and chemokine responses and allergic airway inflammation. We found that type 2 cytokine responses (IL-4, IL-5 and IL-13) are significantly decreased in p110d mutants, whereas type 1 cytokine responses (IFN-c and CXCL10) were robust. Elevated IFN-c production during the primary response to ovalbumin (OVA) was associated with reduced production of the regulatory cytokine IL-10. IFN-c and IL-10 production normalized after secondary OVA immunization; however, type 2 cytokine production was persistently reduced. Type 2 cytokine-dependent airway inflammation elicited by intranasal challenge with OVA was dramatically reduced, with reduced levels of eosinophil recruitment and mucus production observed in the lungs. Induction of respiratory hyper-responsiveness to inhaled methacholine, a hallmark of asthma, was markedly attenuated in p110d-inactivated mice. Adoptive transfer of OVA-primed splenocytes from normal but not p110d-inactivated mice could induce airway eosinophilia in naive, airway-challenged recipient mice. These data demonstrate a novel functional role for p110d signaling in induction of type 2 responses in vivo and may offer a new therapeutic target for Th2-mediated airway disease. IntroductionPhosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating immune function [1,2]. PI3K are activated by stimulation through a variety of receptor types, including antigen receptors, costimulatory receptors and certain cytokine receptors. PI3K function by phosphorylating specific plasma membrane phospholipids to generate short-lived, membrane-integral lipid [3,4]. Effects of regulatory subunit deficiencies on T cells are less clear: deficiency of the p85a regulatory subunit for class 1A PI3K was reported to have no effect on T cell activation in vitro, while deficiency in the p85b regulatory subunit increased T cell proliferation in vitro [5]. One group found that p85-deficient mice have enhanced responses to Leishmania infection [6], but reduced immunity to nematode infection [7], suggesting that impaired class IA PI3K signaling leads to an immune dysregulation rather than a general immunodeficiency. However, the interpretation of these studies is complicated because regulatory subunits each affect the stability and activity of multiple catalytic subunits and may have adaptor functions in signaling independent of PI3K catalytic subunits.Recent work has begun to explore the specific roles of different PI3K catalytic subunit isoforms in immune function. Analysis of p110a and p110b deficiency has been hindered by the lethality of these mutations [8,9]. Mice deficient in the class IB subunit p110c are viable and have defects in T cell development and activation, as well as severe defects in neutrophil function, while B cell activation appears normal [1...

show abstract

A Crucial Role for the p110δ Subunit of Phosphatidylinositol 3-Kinase in B Cell Development and Activation

Cited by 418 publications

References 61 publications

Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation

Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation

Impaired B‐1 and B‐2 B cell development and atypical splenic B cell structures in IL‐7 receptor‐deficient mice

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

Contact Info

Product

Resources

About