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Full Activation (full + activation)
Selected AbstractsMyeloid-derived suppressor cells in inflammation: Uncovering cell subsets with enhanced immunosuppressive functionsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2009Vincenzo Bronte Abstract Although originally described in tumor-bearing hosts, myeloid-derived suppressor cells (MDSC) have been detected under numerous pathological situations that cause enhanced demand of myeloid cells. Thus, MDSC might be part of a conserved response to different endogenous and exogenous stress signals, including inflammation. Two processes are fundamental for MDSC biology: differentiation from myeloid progenitors and full activation of their immune regulatory program by factors released from activated T cells or present in the microenvironment conditioned by either tumor growth or inflammation. How these two processes are controlled and linked is still an open question. In this issue of the European Journal of Immunology, a paper demonstrates that a combination of the known inflammatory molecules, IFN-, and LPS, sustains MDSC expansion and activation while suppressing differentiation of DC from bone marrow precursors. Moreover, this paper contributes to defining the cell subsets that possess immunoregulatory properties within the broad population of CD11b+Gr-1+ cells, often altogether referred to as MDSC. [source] Efficient help for autoreactive B-cell activation requires CD4+ T-cell recognition of an agonist peptide at the effector stageEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2009Brian D. Hondowicz Abstract T-cell recognition of peptide/MHC complexes is flexible and can lead to differential activation, but how interactions with agonist (full activation) or partial agonist (suboptimal activation) peptides can shape immune responses in vivo is not well characterized. We investigated the effect of stimulation by agonist or partial agonist ligands during initial CD4+ T-cell priming, and subsequent T-B-cell cognate interactions, on antibody production by anti-chromatin B cells. We found that autoantibody production required TCR recognition of an agonist peptide at the effector stage of B-cell activation. However, interaction with a weak agonist ligand at this effector stage failed to promote efficient autoantibody production, even if the CD4+ T cells were fully primed by an agonist peptide. These studies suggest that the reactivity of the TCR for a target self-peptide during CD4+ T-B-cell interaction can be a critical determinant in restraining anti-chromatin autoantibody production. [source] CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2005Anja Marschner Abstract Human V,24+ V,11+ natural killer T cells (NKT cells) are "natural memory" T cells that detect glycolipid antigens such as ,-galactosylceramide (,-GalCer) presented on CD1d. In the present study we found that highly purified V,24+ NKT cells lack TLR9 mRNA, and thus are not sensitive towards stimulation with CpG oligodeoxynucleotides (ODN). Within PBMC, however, CpG ODN synergistically activated NKT cells stimulated with their cognate antigen ,-GalCer. Depletion of plasmacytoid dendritic cells (PDC) or myeloid dendritic cells (MDC) revealed that both DC subsets were necessary for the synergistic activation of NKT cells by ,-GalCer and CpG ODN. While PDC were responsible for the stimulation of NKT cells with CpG ODN, MDC but not PDC presented ,-GalCer via CD1d. Partial activation of NKT cells was mediated by PDC-derived IFN-,, whereas full activation of NKT cells as indicated by IFN,, production required cell-to-cell contact of PDC and NKT cells in addition to IFN-,; OX40 was involved in this interaction. We conclude that CpG-activated PDC enhance ,-GalCer-specific NKT cell activation, and bias activated NKT cells towards a Th1 phenotype. Our results lead to a novel concept of PDC function: to regulate effector activity of antigen-stimulated T cells in a cell contact-dependent manner without the need of simultaneous presentation of the cognate T cell antigen. [source] Pathophysiologic importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in miceHEPATOLOGY, Issue 5 2000Judy A. Lawson Neutrophils can cause parenchymal cell injury in the liver during ischemia-reperfusion and endotoxemia. Neutrophils relevant for the injury accumulate in sinusoids, transmigrate, and adhere to hepatocytes. To investigate the role of E- and L-selectin in this process, C3Heb/FeJ mice were treated with 700 mg/kg galactosamine and 100 ,g/kg endotoxin (Gal/ET). Immunogold labeling verified the expression of E-selectin on sinusoidal endothelial cells 4 hours after Gal/ET injection. In addition, Gal/ET caused up-regulation of Mac-1 (CD11b/CD18) and shedding of L-selectin from circulating neutrophils. Gal/ET induced hepatic neutrophil accumulation (422 ± 32 polymorphonuclear leukocytes [PMN]/50 high power fields [HPF]) and severe liver injury (plasma alanine transaminase [ALT] activities: 4,120 ± 960 U/L; necrosis: 44 ± 3%) at 7 hours. Treatment with an anti,E-selectin antibody (3 mg/kg, intravenously) at the time of Gal/ET administration did not significantly affect hepatic neutrophil accumulation and localization. However, the anti,E-selectin antibody significantly attenuated liver injury as indicated by reduced ALT levels (,84%) and 43% less necrotic hepatocytes. In contrast, animals treated with an anti,L-selectin antibody or L-selectin gene knock out mice were not protected against Gal/ET-induced liver injury. However, E-, L-, and P-selectin triple knock out mice showed significantly reduced liver injury after Gal/ET treatment as indicated by lower ALT levels (,65%) and reduced necrosis (,68%). Previous studies showed that circulating neutrophils of E-selectin,overexpressing mice are primed and activated similar to neutrophils adhering to E-selectin in vitro. Therefore, we conclude that blocking E-selectin or eliminating this gene may have protected against Gal/ET-induced liver injury in vivoby inhibiting the full activation of neutrophils during the transmigration process. [source] Granzyme B: a natural born killerIMMUNOLOGICAL REVIEWS, Issue 1 2003Sarah J. Lord Summary:, A main pathway used by cytotoxic T lymphocytes (CTLs) and natural killer cells to eliminate pathogenic cells is via exocytosis of granule components in the direction of the target cell, delivering a lethal hit of cytolytic molecules. Amongst these, granzyme B and perforin have been shown to induce CTL-mediated target cell DNA fragmentation and apoptosis. Once released from the CTL, granzyme B binds its receptor, the mannose-6-phosphate/insulin-like growth factor II receptor, and is endocytosed but remains arrested in endocytic vesicles until released by perforin. Once in the cytosol, granzyme B targets caspase-3 directly or indirectly through the mitochondria, initiating the caspase cascade to DNA fragmentation and apoptosis. Caspase activity is required for apoptosis to occur; however, in the absence of caspase activity, granzyme B can still initiate mitochondrial events via the cleavage of Bid. Recent work shows that granzyme B-mediated release of apoptotic factors from the mitochondria is essential for the full activation of caspase-3. Thus, granzyme B acts at multiple points to initiate the death of the offending cell. Studies of the granzyme B death receptor and internal signaling pathways may lead to critical advances in cell transplantation and cancer therapy. [source] Kinetic perspectives of T cell antigen receptor signalingIMMUNOLOGICAL REVIEWS, Issue 1 2003Makio Iwashima Summary: T-cell activation consists of multiple layers of signaling events. Interleukin-2 production is of interest for many, since its expression determines a critical difference between partial and full T-cell activation. To achieve full activation of T cells, it is necessary for the T-cell antigen receptor (TCR) to be engaged for an extended period of time. However, why extended stimulation is required for full T-cell activation is not understood at the molecular level. In this review, orchestrated events of TCR signal transduction will be analyzed in a kinetic manner and connected toward the understanding of the mechanism of T-cell activation. Based on recent results, a model of the mechanism that dictates the threshold between partial and full T-cell activation is proposed. [source] Signalling events involved in interferon-,-inducible macrophage nitric oxide generationIMMUNOLOGY, Issue 4 2003Julie Blanchette Summary Nitric oxide (NO) produced by macrophages (M,) in response to interferon-, (IFN-,) plays a pivotal role in the control of intracellular pathogens. Current knowledge of the specific biochemical cascades involved in this IFN-,-inducible M, function is still limited. In the present study, we evaluated the participation of various second messengers , Janus kinase 2 (JAK2), signal transducer and activator of transcription (STAT) 1,, MAP kinase kinase (MEK1/2), extracellular signal-regulated kinases 1 and 2 (Erk1/Erk2) and nuclear factor kappa B (NF-,B) , in the regulation of NO production by IFN-,-stimulated J774 murine M,. The use of specific signalling inhibitors permitted us to establish that JAK2/STAT1,- and Erk1/Erk2-dependent pathways are the main players in IFN-,-inducible M, NO generation. To determine whether the inhibitory effect was taking place at the pre- and/or post-transcriptional level, we evaluated the effect of each antagonist on inducible nitric oxide synthase (iNOS) gene and protein expression, and on the capacity of IFN-, to induce JAK2, Erk1/Erk2 and STAT1, phosphorylation. All downregulatory effects occurred at the pretranscriptional level, except for NF-,B, which seems to exert its role in NO production through an iNOS-independent event. In addition, electrophoretic mobility shift assay (EMSA) analysis revealed that STAT1, is essential for IFN-,-inducible iNOS expression and NO production, whereas the contribution of NF-,B to this cellular regulation seems to be minimal. Moreover, our data suggest that Erk1/Erk2 are responsible for STAT1, Ser727 residue phosphorylation in IFN-,-stimulated M,, thus contributing to the full activation of STAT1,. Taken together, our results indicate that JAK2, MEK1/2, Erk1/Erk2 and STAT1, are key players in the IFN-,-inducible generation of NO by M,. [source] Effects of sequential exposure to lipopolysaccharide and heat stress on dental pulp cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2006Chiaki Kitamura Abstract In the present study, we examined the effects of sequential exposure to bacterial lipopolysaccharide (LPS) and heat stress on dental pulp cells. LPS induced the proliferation of pulp cells through the activation of p38 MAPK. HSP27 was expressed in cells with or without LPS during the entire period of heat stress, while transiently phosphorylated by short-term heat stress. In LPS-treated cells, short-term heat stress also induced the phosphorylation of HSF1. The immediate phosphorylation of HSF1 and HSP27 in LPS-treated cells by short-term heat stress occurred dependent on the activation of p38 MAPK. However, with long-term heat stress, the activation of HSF1 and induction of HSP27 occurred independent of p38 MAPK. Further, full activation of Akt in LPS-treated cells was immediately induced by short-term heat stress and lasted during the entire period of heat stress. I,B, was induced and phosphorylated throughout sequential exposure to LPS and heat stress. These results suggest that LPS has the unique effects on the cytoprotection and the cell death of pulp cells during heat stress through the modification and the activation of heat stress responsive molecules, HSF1 and HSP27, and cell survival molecules, Akt and NF-,B/I,B,. J. Cell. Biochem. 99: 797,806, 2006. © 2006 Wiley-Liss, Inc. [source] Lipid rafts are required in G,i signaling downstream of the P2Y12 receptor during ADP-mediated platelet activationJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2005T. M. QUINTON Summary., ADP is important in propagating hemostasis upon its secretion from activated platelets in response to other agonists. Lipid rafts are microdomains within the plasma membrane that are rich in cholesterol and sphingolipids, and have been implicated in the stimulatory mechanisms of platelet agonists. We sought to determine the importance of lipid rafts in ADP-mediated platelet activation via the G protein-coupled P2Y1 and P2Y12 receptors using lipid raft disruption by cholesterol depletion with methyl- , -cyclodextrin. Stimulation of cholesterol-depleted platelets with ADP resulted in a reduction in the extent of aggregation but no difference in the extent of shape change or intracellular calcium release. Furthermore, repletion of cholesterol to previously depleted membranes restored ADP-mediated platelet aggregation. In addition, P2Y12-mediated inhibition of cAMP formation was significantly decreased upon cholesterol depletion from platelets. Stimulation of cholesterol-depleted platelets with agonists that depend upon G,i activation for full activation displayed significant loss of aggregation and secretion, but showed restoration when simultaneously stimulated with the G,z -coupled agonist epinephrine. Finally, G,i preferentially localizes to lipid rafts as determined by sucrose density centrifugation. We conclude that G,i signaling downstream of P2Y12 activation, but not G,q or G,z signaling downstream of P2Y1 or ,2A activation, respectively, has a requirement for lipid rafts that is necessary for its function in ADP-mediated platelet activation. [source] Tethering of CpxP to the inner membrane prevents spheroplast induction of the Cpx envelope stress responseMOLECULAR MICROBIOLOGY, Issue 5 2000Tracy L. Raivio The Cpx envelope stress response of Escherichia coli is controlled by a two-component regulatory system that senses misfolded proteins in extracytoplasmic compartments and responds by inducing the expression of envelope protein folding and degrading factors. We have proposed that in the absence of envelope stress the pathway is maintained in a downregulated state, in part through interactions between the periplasmic inhibitor molecule CpxP and the sensing domain of the histidine kinase CpxA. In this study, we show that depletion of the periplasmic contents of the cell by spheroplast formation does indeed lead to induction of the Cpx envelope stress response. Further, removal of CpxP is an important component of this induction because tethering an MBP,CpxP fusion protein to the spheroplast inner membranes prevents full activation by this treatment. Spheroplast formation has previously been demonstrated to induce the expression of a periplasmic protein of unknown function, Spy. Analysis of spy expression in response to spheroplast formation by Western blot analysis and by lacZ operon fusion in various cpx mutant backgrounds demonstrated that spy is a member of the Cpx regulon. Interestingly, although the only known spy homologue is cpxP, Spy does not appear to perform the same function as CpxP as it is not involved in inhibiting the Cpx envelope stress response. Rather, deletion of spy leads to activation of the ,E stress response. Because the ,E response is specifically affected by alterations in outer membrane protein biogenesis, we think it possible that Spy may be involved in this process. [source] | |||||||||||||