368 research outputs found
IgM-producing tumors in the BALB/c mouse: a model for B-cell maturation
Five adjuvant induced BALB/c tumors producing IgM—McPc 1748, W 3469, TEPC 183, McPc 774, and Y 5781—were characterized morphologically by electron microscopy, analysis of the distribution of surface-bound and intracytoplasmic IgM using immunofluorescence, and by biochemical study of IgM synthesis, turnover, and secretion. The cells of different tumors appear to represent different stages in B-cell maturation when compared to normal, lipopolysaccharide-stimulated B cells. Thus, McPc 1748 tumor cells resemble 10–25-h stimulated normal B cells, 3469 cells resemble 20–35-h stimulated B cells, TEPC 183 cells resemble 45–65-h stimulated B cells, Y 5781 cells resemble 80–110-h stimulated B cells, and McPc 774 cells resemble 100–130-h stimulated B cells
Regulation of Lymphocyte Apoptosis by Interferon Regulatory Factor 4 (IRF-4)
To ensure that homeostasis of the immune system is maintained, the sensitivity of lymphocytes to Fas-mediated apoptosis is differentially regulated during their activation. The molecular mechanisms that link the activation program of lymphocytes to changes in sensitivity to Fas-mediated apoptosis have, however, not been fully characterized. In these studies, we have investigated whether Fas-mediated apoptosis can be regulated by interferon regulatory factor 4 (IRF-4), a lymphoid-restricted member of the IRF family of transcription factors. IRF-4 expression is upregulated during lymphocyte activation and IRF-4–deficient mice have defects in both lymphocyte activation and homeostasis. Here, we show that stable expression of IRF-4 in a human lymphoid cell line that normally lacks IRF-4 leads to a significantly enhanced apoptotic response on Fas receptor engagement. A systematic examination of the downstream effectors of Fas signaling in IRF-4–transfected cells demonstrates an increased activation of caspase-8, as well as an increase in Fas receptor polarization. We demonstrate that IRF-4–deficient mice display defects in activation-induced cell death, as well as superantigen-induced deletion, and that these defects are accompanied by impairments in Fas receptor polarization. These data suggest that IRF-4, by modulating the efficiency of the Fas-mediated death signal, is a novel participant in the regulation of lymphoid cell apoptosis
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Modulation of T Cell Cytokine Production by Interferon Regulatory Factor-4
Production of cytokines is one of the major mechanisms employed by CD4(+) T cells to coordinate immune responses. Although the molecular mechanisms controlling T cell cytokine production have been extensively studied, the factors that endow T cells with their ability to produce unique sets of cytokines have not been fully characterized. Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4(+) T cells to produce cytokines. In these studies, we have investigated the mechanisms employed by IRF-4 to control cytokine synthesis. We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13. Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter. A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1. These studies thus support the notion that IRF-4 represents one of the lymphoid-specific components that control the ability of T lymphocytes to produce a distinctive array of cytokines
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Molecular cloning of IBP, a SWAP-70 homologous GEF, which is highly expressed in the immune system
Rho GTPases play a fundamental role in a variety of biological processes ranging from the reorganization of the actin cytoskeleton to the regulation of cell proliferation. The activation of Rho GTPases is regulated by guanine nucleotide exchange factors (GEFs) belonging to the Dbl family of proteins. The hallmark of this large family of GEFs is the presence of a tandem DH-PH module in which a pleckstrin-homology (PH) domain is located at the C-terminus of a Dbl-homology (DH) domain. Recent studies have demonstrated that SWAP-70 constitutes a novel class of Rac-GEF, in which the PH domain is located at the N-terminus, rather than the C terminus, of the DH domain. Here we report the molecular cloning of human IBP (IRF-4 binding protein), a new member of this novel family of GEFs. The IBP gene maps to human chromosome 6p21.31 centromeric to the MHC locus. Isolation of the murine IBP cDNA reveals a very high degree of homology with the human IBP cDNA suggesting that IBP is evolutionarily conserved. The 5′ portion of the murine IBP cDNA is furthermore identical to the Def-6 cDNA fragment, which was identified in the course of a search for genes differentially expressed in the murine hematopoietic system. IBP is broadly expressed in the immune system and can be detected in both T and B cell compartments in contrast to SWAP-70 whose expression is primarily restricted to B cells. Taken together these findings indicate that IBP is a novel type of GEF, which participates in the activation of Rho GTPases in lymphoid tissues
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T Cell Receptor Engagement Leads to the Recruitment of IBP, a Novel Guanine Nucleotide Exchange Factor, to the Immunological Synapse
Reorganization of the actin cytoskeleton is crucial to the formation and function of the immunological synapse. Rho GTPases are critical mediators of cytoskeletal reorganization, and their activity at the synapse is likely to be stringently regulated. Guanine nucleotide exchange factors (GEFs) belonging to the Dbl family of proteins represent one major class of proteins that regulate the activity of Rho GTPases. Here we demonstrate that IBP, a homologue of SWAP-70, is a novel GEF for Rac1 and Cdc42 in T lymphocytes, which is recruited to the immunological synapse upon engagement of the antigen receptor. Mutational analysis supports a model whereby IBP is inactive in unstimulated cells. Upon engagement of the T cell receptor, its GEF activity is enhanced by tyrosine phosphorylation, as well as by binding newly generated phosphatidylinositol 3,4,5-trisphosphate. Although it is known that T cell receptor engagement leads to the recruitment of Vav to the immunological synapse, these findings indicate that other GEFs, such as IBP, also relocalize to this intercellular region. The recruitment and activation of distinct classes of GEFs may allow for precise control of Rho GTPase function at the crucial interface between T cells and antigen presenting cells
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