Dynamic regulation of T cell activation and co-stimulation through TCR-microclusters

Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Japan.
FEBS letters (Impact Factor: 3.34). 12/2010; 584(24):4865-71. DOI: 10.1016/j.febslet.2010.11.036
Source: PubMed

ABSTRACT TCR-microclusters (MC) are generated upon TCR stimulation prior to the immune synapse formation independently of lipid rafts. TCR-MCs contain receptors, kinases and adaptors, and function as the signaling unit for T cell activation. The TCR complex, but not the signaling molecules, is transported to the center to form cSMAC. The co-stimulation receptor CD28 joins the signaling region of cSMAC and recruits PKCθ and Carma1. CTLA-4 accumulates in the same region and competes with CD28 for negative regulation of T cell activation. T cell activation is therefore mediated by two spatially distinct signaling compartments: TCR signaling by the peripheral TCR-MC and co-stimulation signal by the central signaling cSMAC.

Download full-text


Available from: Takashi Saito, Apr 28, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Degradation in CMOS inverter circuit performance as a result of gate oxide wearout in 2.0 nm pMOSFETs was investigated using a constant voltage stress (CVS) technique. It is demonstrated that inverter performance in the time-domain shows significant deterioration when only the pMOSFET experiences wearout. Experimental results indicate loss of inverter circuit performance in the time-domain given by approximately 36% to 62% increase in the rise time. Conversely, DC inverter characteristics are potentially misleading showing that inverter performance was only partially altered. In both cases, inverter degradation is related to the pMOSFET suffering as much as a 40% decrease in drive current after wearout. This and other large changes in device parameters are compared to a typical logic process revealing that the device parameters are outside the process window. Ultimately, this study suggests that wearout in ultra-thin gate oxides may lead to increased circuit degradation despite the gate leakage current associated with a known circuit component being lower than that required for a typical or traditional BD event to occur.
    Integrated Reliability Workshop Final Report, 2004 IEEE International; 11/2004
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital toxoplasmosis may lead to several risk factors to pregnant women; as well as to the foetus. Parasitological direct methods and Toxoplasma gondii isolation in vivo and in vitro, from biological samples may constitute an option to diagnostic determination of this disease. For this reason the aim of this study was to observe related results obtained from in vivo and in vitro isolation of Toxoplasma gondii from biological samples of pregnant women (n= 13) showing serological indication of toxoplasmosis, treated (or not) with protocol therapy and also evaluate lesions in the placenta of these pregnant women. To carry out the research, the following methods were used: direct observation of amniotic fluid samples or direct analysis from the centrifuged samples, intraperitoneal inoculation of mice, cell culture inoculation and histopathological analysis of placenta. Tachyzoites were observed both in free and intracellular forms during direct parasitological method, in all amniotic fluid and placenta samples. Parasites were also observed in peritoneal exsudate from inoculated mice since the 10th intraperitoneal passage, with a mantainance period of 55 passages. Nonetheless, cerebral cysts were not seen in any of the inoculated mice, except in one animal that showed neurological distress. During in vitro isolation an average concentration of tachyzoites (222 tachyzoites/mL) in a mean time of 16,7 days was obtained, and during mantainance growth period the average was 1X106 parasites/mL (5 – 6 months). The growth (multiplication) period occurred between 5 -12 months, with a initial average concentration of 6,15 1X107 parasites/mL. Both in vitro and in vivo isolation the parasites showed a less agressive behavior when compared to standard RH-T. gondii and NC-1-N. caninum strains, probably due to several variables like: drugs used in protocol treatment of the pregnant women, physical and chemical stress conditions associated to the technical procedures, strain attenuation during the isolation passages. Significative histopathological alterations were not seen in placental samples. The results obtained in this study revealed vantages and also disadvantages related to the techniques discussed in this article. Key Words: Isolation, in vitro, in vivo, Parasitological Analysis, Histopathological Analysis.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Proteins participating in immunological signaling have emerged as important targets for controlling the immune response. A multitude of receptor-ligand pairs that regulate signaling pathways of the immune response have been identified. In the complex milieu of immune signaling, therapeutic agents targeting mediators of cellular signaling often either activate an inflammatory immune response or induce tolerance. This review is primarily focused on therapeutics that inhibit the inflammatory immune response by targeting membrane-bound proteins regulating costimulation or mediating immune-cell adhesion. Many of these signals participate in larger, organized structures such as the immunological synapse. Receptor clustering and arrangement into organized structures is also reviewed and emerging trends implicating a potential role for multivalent therapeutics is posited.
    Therapeutic delivery 07/2011; 2(7):873-89. DOI:10.4155/tde.11.60
Show more