Impaired B and T Cell Antigen Receptor Signaling in p110δ PI 3-Kinase Mutant Mice

Okkenhaug, Klaus; Bilancio, Antonio; Farjot, Géraldine; Priddle, Helen; Sancho, Sara; Peskett, Emma; Pearce, Wayne; Meek, Stephen; Salpekar, Ashreena; Waterfield, Michael D.; Smith, Andrew J.H.; Vanhaesebroeck, Bart

doi:10.1126/science.1073560

Cited by 866 publications

(1,032 citation statements)

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“…Knockouts of p110a and p110b are embryonic lethals (Bi et al, 1999(Bi et al, , 2002 whereas knockouts of p110d and p110g are viable but show defects in components of the immune response (Sasaki et al, 2000;Okkenhaug et al, 2002). However, because of the tissuespecific expression of the isoforms, the functional information that can be derived from ubiquitous knockouts is limited (reviewed in Vanhaesebroeck et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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The catalytic subunits of class I PI3Ks comprise four isoforms: p110a, p110b, p110d and p110c. Cancer-specific gain-of-function mutations in p110a have been identified in various malignancies. Cancer-specific mutations in the non-a isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110b, p110c or p110d is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-a isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3b and cause degradation of FoxO1. A functional Erk pathway is required for p110c and p110b transformation but not for transformation by p110d or the H1047R mutant of p110a. Transformation and signaling by p110c and p110b are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110d reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110b and p110c.

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Section: Introductionmentioning

confidence: 99%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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“…We have used a targeted mutagenesis approach to generate mice expressing normal levels of p110d bearing an inactivating point mutation in the kinase domain [11]. 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].…”

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confidence: 99%

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

et al. 2007

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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...

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“…The essential tasks of p85a in T-and B-cell development and function have been extensively characterized. [19][20][21] Using p85a À/À mice, we demonstrate that p85a, p55a and p50a are crucial for NK cell lineage commitment, terminal maturation, cytokine/chemokine generation and cytotoxicity.…”

Section: Discussionmentioning

confidence: 86%

“…p85a, p55a and p50a are highly expressed in NK cells Regulatory p85a along with the catalytic p110d subunit is important in the development and functions of T and B cells. [19][20][21] Deletion of p85a/p55a/p50a severely impaired the functions of these immune cells. To assess its potential role in NK cells, we first examined its protein expression.…”

Section: Resultsmentioning

confidence: 99%

“…Class 1A phosphotidylinositol-3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that generate critical second messengers downstream of T-and B-cell antigen receptors. [19][20][21] PI3K-p85a gene gives rise to two other alternatively spliced isoforms, p55a and p50a, which also participate in p85a-mediated signaling. p85a is a ubiquitously expressed subunit, which binds to one of the p110 catalytic isoforms (p110a, p110b or p110d).…”

Section: Introductionmentioning

confidence: 99%

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Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

et al. 2008

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Class IA phosphotidylinositol-3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that are important in regulating signaling events in B and T cells. However, their role in natural killer (NK) cells is not understood. Here, using mice that lack the regulatory p85a subunit and its alternatively spliced variants p55a/p50a (collectively termed as p85a À/À ), we defined the role of PI3K in NK cell development and function. p85a À/À mice had impaired lineage commitment leading to reduced NK cellularity in the bone marrow and liver. p85a À/À NK cells showed a defective Ly49 subset specification and a decreased expression of CD43. Lack of p85a severely reduced the NK-mediated cytotoxicity against tumor cells representing 'induced-self' and 'missing-self'. More importantly, NKG2D and NK1.1 receptor-mediated cytokine and chemokine generation was significantly compromised in p85a À/À NK cells. These results reveal a previously unrecognized role of p85a in the development, terminal maturation, cytokine/chemokine generation and tumor clearance of NK cells.

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Impaired B and T Cell Antigen Receptor Signaling in p110δ PI 3-Kinase Mutant Mice

Cited by 866 publications

References 21 publications

Oncogenic signaling of class I PI3K isoforms

Oncogenic signaling of class I PI3K isoforms

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

Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

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