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The large mucin CD43 is actively excluded from T cell/APC interaction sites, concentrating in a membrane domain distal to the site of TCR engagement. The cytoplasmic region of CD43 was necessary and sufficient for this antipodal movement. ERM cytoskeletal adaptor proteins colocalized with CD43 in this domain. An ERM dominant-negative mutant blocked the distal accumulation of CD43 and another known...
The positive selection of CD4 or CD8 single-positive mature peripheral T lymphocytes and the deletion of self-reactive cells are crucial for central tolerance in the peripheral immune system. Previously, the guanine nucleotide binding protein Rac-1 has been shown to control pre-T cell development. The present report now describes the actions of Rac-1 in thymocyte selection. The study reveals that...
TWEAK is a member of the TNF ligand family that induces angiogenesis in vivo. We report cloning of a receptor for TWEAK (TweakR) from a human umbilical vein endothelial cell (HUVEC) library. The mature form of TweakR has only one hundred and two amino acids and six cysteine residues in its extracellular region. Five different assays demonstrate TWEAK-TweakR binding, and the interaction affinity constant...
One mechanism cytotoxic T lymphocytes use to kill targets is exocytosis of cytotoxic agents from lytic granules, a process that requires Ca 2+ influx. We investigated the role of Ca 2+ influx in granule exocytosis using TALL-104 human leukemic cytotoxic T cells triggered via a bispecific antibody containing an anti-CD3 F(ab') to kill Raji B lymphoma cells. Using a novel fluorescence...
Cytotoxic T lymphocytes (CTL) rapidly destroy their targets. Here we show that although target cell death occurs within 5 min of CTL-target cell contact, an immunological synapse similar to that seen in CD4 cells rapidly forms in CTL, with a ring of adhesion proteins surrounding an inner signaling molecule domain. Lytic granule secretion occurs in a separate domain within the adhesion ring, maintaining...
The major murine systemic lupus erythematosus (SLE) susceptibility locus, Sle1, corresponds to three loci independently affecting loss of tolerance to chromatin in the NZM2410 mouse. The congenic interval corresponding to Sle1c contains Cr2, which encodes complement receptors 1 and 2 (CR1/CR2, CD35/CD21). NZM2410/NZW Cr2 exhibits a single nucleotide polymorphism that introduces a novel glycosylation...
The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes...
The proinflammatory cytokine interleukin-1β (IL-1β) is a secreted protein that lacks a signal peptide and does not follow currently known pathways of secretion. Its efficient release from activated immune cells requires a secondary stimulus such as extracellular ATP acting on P2X 7 receptors. We show that human THP-1 monocytes shed microvesicles from their plasma membrane within 2-5 s of activation...
Dynamic interactions between membrane and cytoskeleton components are crucial for T cell antigen recognition and subsequent cellular activation. We report here that the membrane-microfilament linker ezrin plays an important role in these processes. First, ezrin relocalizes to the contact area between T cells and stimulatory antigen-presenting cells (APCs), accumulating in F-actin-rich membrane protrusions...
The interaction between the TNF receptor family member CD27 and its ligand CD70 provides a costimulatory signal for T cell expansion. Normally, tightly regulated expression of CD70 ensures the transient availability of this costimulatory signal. Mice expressing constitutive CD70 on B cells had higher peripheral T cell numbers that showed increased differentiation toward effector-type T cells. B cell...
Formation of the immunological synapse requires TCR signal-dependent protein redistribution. However, the specific molecular mechanisms controlling protein relocation are not well defined. Moesin is a widely expressed phospho-protein that links many transmembrane molecules to the cortical actin cytoskeleton. Here, we demonstrate that TCR-induced exclusion of the large sialoprotein CD43 from the synapse...
Viruses have evolved elaborate mechanisms to target many aspects of the host's immune response. The cytokine IFN-γ plays a central role in resistance of the host to infection via direct antiviral effects as well as modulation of the immune response. In this study, we demonstrate that the Epstein-Barr virus (EBV) immediate-early protein, BZLF1, inhibits the IFN-γ signaling pathway. BZLF1 decreases...
The IL-7 receptor (IL-7R) plays critical roles in expansion and V(D)J recombination during lymphocyte development. Here we demonstrate that cytokine stimulation rapidly recruits Stat5 and transcriptional coactivators to the Jγ germline promoter and induces histone acetylation, germline transcription, and accessibility in Ba/F3 cells. We also show that histone acetylation of the TCRγ locus is significantly...
HIV-1 budding appears to require Vps4 and Tsg101-two proteins that have links to endosomal sorting machinery. A picture emerges wherein divergent viruses recruit endosomal proteins like Tsg101 to gain access to ubiquitin processes that play a crucial role during viral budding.
The immunological synapse is characterized by the reorganization of membrane proteins at the immunological synapse. Active cytoskeletal mechanisms are involved in recruiting the TCR, accessory molecules, and the integrin LFA-1 to the contact area. Other molecules like CD43 are excluded from the contact area, but the mechanism of exclusion is unknown. Three papers in this issue of Immunity demonstrate...
Here we show that activated Th1 and Th2 cells have distinct patterns of membrane compartmentalization into lipid rafts. TCR complex members are recruited efficiently to rafts and aggregate with rafts at the site of MHC/peptide contact in Th1 cells but not Th2 cells. TCR/raft association in Th1 cells is deficient in the absence of CD4, suggesting that CD4 aids recruitment of the TCR to rafts. We show...
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