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ABSTRACT: The inositol phosphatases phosphatase and tensin homologue (PTEN) and Src homology 2 domain-containing inositol phosphatase (SHIP) negatively regulate phosphatidylinositol-3-kinase (PI3K)-mediated growth, survival, and proliferation of hematopoietic cells. Although deletion of PTEN in mouse T cells results in lethal T cell lymphomas, we find that animals lacking PTEN or SHIP in B cells show no evidence of malignancy. However, concomitant deletion of PTEN and SHIP (bPTEN/SHIP(-/-)) results in spontaneous and lethal mature B cell neoplasms consistent with marginal zone lymphoma or, less frequently, follicular or centroblastic lymphoma. bPTEN/SHIP(-/-) B cells exhibit enhanced survival and express more MCL1 and less Bim. These cells also express low amounts of p27(kip1) and high amounts of cyclin D3 and thus appear poised to undergo proliferative expansion. Unlike normal B cells, bPTEN/SHIP(-/-) B cells proliferate to the prosurvival factor B cell activating factor (BAFF). Interestingly, although BAFF availability may promote lymphoma progression, we demonstrate that BAFF is not required for the expansion of transferred bPTEN/SHIP(-/-) B cells. This study reveals that PTEN and SHIP act cooperatively to suppress B cell lymphoma and provides the first direct evidence that SHIP is a tumor suppressor. As such, assessment of both PTEN and SHIP function are relevant to understanding the etiology of human B cell malignancies that exhibit augmented activation of the PI3K pathway.
Journal of Experimental Medicine 10/2010; 207(11):2407-20. · 13.85 Impact Factor
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Matthew H. Cato,
Federica D'Annibale, David M. Mills,
Fabio Cerignoli,
Marcia I. Dawson,
Enrico Bergamaschi,
Nunzio Bottini,
Andrea Magrini,
Antonio Bergamaschi,
Nicola Rosato,
Robert C. Rickert,
Tomas Mustelin,
Massimo Bottini
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ABSTRACT: In this paper we report the fabrication of a multivalent, cell-type specific and cytoplasmic delivery system based on single-walled carbon nanotubes. The latter were functionalized through adsorption of phospholipids terminated by biotinylated PEG chains functionalized with fluorochrome-coupled neutravidin, and subsequently with antibodies (anti-CD3ε and anti-CD28) for T cell receptor post-signaling endocytosis and a synthetic fusogenic polymer for disruption of lysosomal compartments. The biomimetic nanoassemblies were composed by PEGylated individual/very small bundles of carbon nanotubes having an average length and a standard deviation of 176 nm and 77 nm, respectively. The nanoassemblies were stably dispersed under physiological conditions, visible by conventional optical and confocal microscopy and specifically targeted to T cells both in vitro and in living animals. The addition of a fusogenic polymer to the nanoassemblies did not affect the cellular uptake and allowed the release into the cytosol of the targeted cells both in vitro and in the animals. The present manuscript is the first report about the cytoplasmic delivery of carbon nanotubes in a specific cell type in intact animals and paves the way for their use as in vivo intracellular delivery systems.
Journal of Nanoscience and Nanotechnology 04/2008; 8(5):2259-2269. · 1.56 Impact Factor
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ABSTRACT: We report the fabrication and characterization of neutravidin-conjugated silica nanobeads doped with a ruthenium-complex luminophore and functionalized with antihuman CD3, antihuman CD28, and an acid-sensitive polymer. We observed that the nanobeads were readily delivered into Jurkat T leukemia cells by endocytosis, transported into lysosomes and subsequently into the cytoplasm as revealed by pH-sensitive luminescence. Since signs of cytotoxicity were not observed, the reported nanobeads could be an excellent and nontoxic building block for efficient intracellular transporters.
Journal of the American Chemical Society 07/2007; 129(25):7814-23. · 9.91 Impact Factor
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ABSTRACT: NF-kappaB-inducing kinase (NIK)-mediated IKKalpha phosphorylation activates the alternative NF-kappaB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-betaR, BAFF-R, and CD40. Although NIK, IKKalpha, and p52 are all critical regulators of LT-betaR signaling in stromal cells during humoral immune responses, lymphocytes require NIK, but not p52, for optimal Ig production. This disparity suggests that NIK possesses critical cell-type-specific functions that do not depend on NF-kappaB. Here we use mice bearing targeted mutations of the IKKalpha activation loop Ser(176/180) (IKKalpha(AA)) to address the B cell-intrinsic functions of NIK-IKKalpha signaling in vivo. We find that IKKalpha(AA) B cells mount normal primary antibody responses but do not enter germinal centers. This defect likely derives from ineffective early T-B cell collaboration and leads to impaired generation of humoral memory and relatively short-lived, low-affinity antibody production. Our findings contrast with those obtained by using p52(-/-) B cells, which mount normal Ig responses, and alymphoplasia (NIK mutant) B cells, which produce very little primary Ig. Thus, the NIK-IKKalpha-p52 axis is not as linear and exclusive as previous studies suggest, and IKKalpha possesses critical NF-kappaB-independent functions in B cells.
Proceedings of the National Academy of Sciences 04/2007; 104(15):6359-64. · 9.68 Impact Factor
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Advances in experimental medicine and biology 02/2007; 596:139-48. · 1.09 Impact Factor
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ABSTRACT: Exposure of naïve B cells to the cytokine interleukin-4 (IL-4) and/or antigen leads to a state of "priming," in which subsequent aggregation of major histocompatibility complex class II molecules induces the mobilization of calcium ions and cell proliferation. However, it is not clear how critical this priming is for immune responses or how it is normally induced in vivo. Injection of mice with the commonly used adjuvant alum led to priming of splenic B cells and to the accumulation in the spleen of a previously unknown population of IL-4-producing, Gr1+ cells. These cells and IL-4 were both required for in vivo priming and expansion of antigen-specific B cells, as well as for optimal production of antibody. These studies reveal a key role for a previously unknown accessory myeloid cell population in the generation of humoral immune responses.
Science 07/2004; 304(5678):1808-10. · 31.20 Impact Factor
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ABSTRACT: Recent studies demonstrate that MHC class II molecules can signal via associated Ig-alphabeta dimers, signal transducers previously thought to function only in B cell Ag receptor (BCR) signaling. Surprisingly, the biologic outputs of MHC class II and BCR ligation (by thymus-dependent Ags) differ, e.g., MHC class II signaling leads to robust proliferation and extension of pseudopods. It seemed possible that these differences might be due, at least in part, to differential use of inhibitory coreceptors thought to modulate membrane Ig signals. In this study, we demonstrate that CD22, an inhibitory BCR coreceptor, neither associates with nor functions in MHC class II/Ig-alphabeta signaling. Interestingly, CD22 is actively excluded from cell surface MHC class II aggregates.
The Journal of Immunology 02/2004; 172(1):195-201. · 5.79 Impact Factor
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ABSTRACT: Productive interaction between T and B lymphocytes is required for humoral immune responses to many foreign protein antigens and production of pathogenic antibodies characteristic of several autoimmune conditions. Thus, much attention has been given in recent years to understand the dynamic molecular interactions and signal transduction required for productive T-B interaction. In this review we highlight current knowledge of signaling and biologic responses that occur in B cells during cognate interactions with helper T cells, focusing on the dynamic function of B cell-surface molecules in T-B synapses.
Seminars in Immunology 01/2004; 15(6):325-9. · 6.39 Impact Factor
