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Inhibitory Signals (inhibitory + signal)
Selected AbstractsManipulation of NK cytotoxicity by the IAP family member LivinEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2007Boaz Nachmias Abstract Natural killer (NK) cells are part of the innate immune system, capable of killing tumor and virally infected cells. NK cells induce apoptosis in the target cell by either granule- or receptor-mediated pathways. A set of inhibitory and activation ligands governs NK cell activation. As transformed cells often attempt to evade NK cell killing, up-regulation of a potential anti-apoptotic factor should provide a survival advantage. The inhibitor of apoptosis protein (IAP) family can inhibit apoptosis induced by a variety of stimuli. We have previously described a new IAP family member, termed Livin, which has two splice variants (, and ,) with differential anti-apoptotic activities. In this study, we explore the ability of Livin to inhibit NK cell-induced killing. We demonstrate that Livin,, moderately protects against NK cell killing whereas Livin,, augments killing. We show that Livin,, inhibition in Jurkat cells is apparent upon concomitant activation of an inhibitory signal, suggesting that Livin augments an extrinsic inhibitory signal rather than functioning as an independent inhibitory mechanism. Finally, we demonstrate that detection of both Livin isoforms in melanoma cells correlates with a low killing rate. To date, this is the first evidence that directly demonstrates the ability of IAP to protect against NK cell-induced apoptosis. [source] Maintenance of CCL5 mRNA stores by post-effector and memory CD8 T cells is dependent on transcription and is coupled to increased mRNA stabilityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2006Antoine Marçais Abstract Immunological memory is associated with the display of improved effector functions by cells of the adaptive immune system. The storage of untranslated mRNA coding for the CCL5 chemokine by CD8 memory cells is a new process supporting the immediate display of an effector function. Here, we show that, after induction during the primary response, high CCL5 mRNA levels are specifically preserved in CD8 T cells. We have investigated the mechanisms involved in the long-term maintenance of CCL5 mRNA levels by memory CD8 T cells. We demonstrate that the CCL5 mRNA half-life is increased in memory CD8 T cells and that these cells constitutively transcribe ccl5 gene. By inhibiting ccl5 transcription using IL-4, we demonstrate the essential role of transcription in the maintenance of CCL5 mRNA stores. Finally, we show that these stores are spontaneously reconstituted when the inhibitory signal is removed, indicating that the transcription of ccl5 is a default feature of memory CD8 T cells imprinted in their genetic program. [source] Regulatory T cells and autoimmune diseaseIMMUNOLOGICAL REVIEWS, Issue 1 2005Silke Paust Summary:, Although T-cell clones bearing T-cell receptors with high affinity for self-peptide major histocompatibility complex (MHC) products are generally eliminated in the thymus (recessive tolerance), the peripheral T-cell repertoire remains strongly biased toward self-peptide MHC complexes and includes autoreactive T cells. A search for peripheral T cells that might exert dominant inhibitory effects on autoreactivity has implicated a subpopulation of CD4+CD25+ T cells called regulatory T cells (Tregs). Here, we discuss the role of cytokines and costimulatory molecules in the generation, maintenance, and function of Tregs. We also summarize evidence for the involvement of Tregs in controlling autoimmune diseases, including type 1 diabetes, experimental autoimmune encephalomyelitis, and inflammatory bowel disease. Last, we discuss our recent definition of the potential role of B7 expressed on activated T-effector cells as a target molecule for Treg-dependent suppression. These observations suggest that the engagement of B7 on effector T cells transmits an inhibitory signal that blocks or attenuates effector T-cell function. We restrict our comments to the suppression mediated by cells within the CD4 lineage; the impact of the cells within the CD8 lineage that may suppress via engagement of Qa-1 on effector T cells is not addressed in this review. [source] Bone morphogenetic proteins 4, 6, and 7 are up-regulated in mouse spinal cord during experimental autoimmune encephalomyelitisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2008Jahan Ara Abstract Although spontaneous remyelination occurs in multiple sclerosis (MS), the extent of myelin repair is often inadequate to restore normal function. Oligodendrocyte precursors remaining in nonremyelinating MS plaques may be restricted by an inhibitory signal. Bone morphogenetic proteins (BMPs) have been implicated as repressors of oligodendrocyte development and inducers of astrogliogenesis. We hypothesized that BMPs are up-regulated in MS lesions and play a role in demyelination and astrogliosis. We examined expression of BMPs in an animal model of MS, chronic experimental autoimmune encephalomyelitis (EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide in C57BL/6 mice. By 14 days postimmunization, compared to those of control mice, the lumbar spinal cords of MOG-peptide EAE mice demonstrated prominent astrogliosis, infiltration of inflammatory cells, and disrupted expression of myelin proteins. Quantitative RT-PCR showed that expression of BMP4, BMP6, and BMP7 mRNA increased 2- to 4-fold in the lumbar spinal cords of animals with symptomatic EAE versus in vehicle-treated and untreated controls on days 14, 21, and 42 postimmunization. BMP2 mRNA expression was not altered. BMP4 mRNA was much more abundant in the spinal cords of all animals than was mRNA encoding BMP2, BMP6, and BMP7. Immunoblot analysis confirmed the increased expression of BMP4 in the EAE animals. Immunohistochemistry revealed increased BMP4 immunoreactivity in areas of inflammation in MOG-peptide EAE animals. BMP4 labeling was mostly limited to macrophages but was sometimes associated with astrocytes and oligodendrocytes. These results indicate that members of the BMP family are differentially expressed in adult spinal cord and are up-regulated during EAE. © 2007 Wiley-Liss, Inc. [source] Combinatorial treatments for promoting axon regeneration in the CNS: Strategies for overcoming inhibitory signals and activating neurons' intrinsic growth stateDEVELOPMENTAL NEUROBIOLOGY, Issue 9 2007Larry I. Benowitz Abstract In general, neurons in the mature mammalian central nervous system (CNS) are unable to regenerate injured axons, and neurons that remain uninjured are unable to form novel connections that might compensate for ones that have been lost. As a result of this, victims of CNS injury, stroke, or certain neurodegenerative diseases are unable to fully recover sensory, motor, cognitive, or autonomic functions. Regenerative failure is related to a host of inhibitory signals associated with the extracellular environment and with the generally low intrinsic potential of mature CNS neurons to regenerate. Most research to date has focused on extrinsic factors, particularly the identification of inhibitory proteins associated with myelin, the perineuronal net, glial cells, and the scar that forms at an injury site. However, attempts to overcome these inhibitors have resulted in relatively limited amounts of CNS regeneration. Using the optic nerve as a model system, we show that with appropriate stimulation, mature neurons can revert to an active growth state and that when this occurs, the effects of overcoming inhibitory signals are enhanced dramatically. Similar conclusions are emerging from studies in other systems, pointing to a need to consider combinatorial treatments in the clinical setting. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007 [source] New assay to detect low-affinity interactions and characterization of leukocyte receptors for collagen including leukocyte-associated Ig-like receptor-1 (LAIR-1)EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2009Lei Jiang Abstract Leukocyte activity is controlled by numerous interactions between membrane receptors and ligands on the cell surface. These interactions are of low affinity making detection difficult. We developed a sensitive assay that could readily detect extremely weak interactions such as that between CD200 and the activating receptor CD200RLa (Kd>500,,M) at the protein level. We used the new technology to screen for interactions of inhibitory receptors for collagens. We confirmed that both human and mouse leukocyte-associated Ig-like receptor-1, and in addition the related inhibitory leukocyte Ig-like receptor subfamily B member 4 (CD85K, Gp49B), bound collagen specifically, whereas other cell surface proteins gave no binding. The monomeric affinities of the interactions were then determined to allow comparison with other leukocyte interactions and indicate conditions when these interactions might lead to inhibitory signals. [source] Interaction of KLRG1 with E-cadherin: New functional and structural insightsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2008Stephan Rosshart Abstract The killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed by memory T cells and NK cells in man and mice. It is frequently used as a cell differentiation marker and members of the cadherin family are ligands for KLRG1. The present study provides new insights into the interaction of mouse KLRG1 with E-cadherin. Firstly, we demonstrate that co-engagement of KLRG1 and CD3/TCR in a spatially linked manner was required for inhibition arguing against the notion that KLRG1-ligation per se transmits inhibitory signals. Secondly, experiments with T cells carrying Y7F-mutant KLRG1 molecules with a replacement of the tyrosine residue to phenylalanine in the single ITIM indicated that the inhibitory activity of KLRG1 is counteracted to some degree by increased interaction of KLRG1+ T cells with E-cadherin expressing target cells. Thirdly, we demonstrate that deletion of the first or the second external domain of E-cadherin abolished reactivity in KLRG1-reporter cell assays. Finally, we made the intriguing observation that KLRG1 formed multimeric protein complexes in T cells in addition to the previously described mono- and dimeric molecules. [source] In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2005Shigekazu Takahashi Abstract Cytotoxic T,lymphocyte antigen-4 (CTLA-4) induces major inhibitory signals for T,cell activation. From analyses of TCR-transgenic (Tg) CTLA-4-deficient mice, it has been believed that CTLA-4 does not affect thymocyte development. To focus upon the in vivo function of CTLA-4 in thymocyte development from a different aspect, we have established Tg mice expressing either full-length CTLA-4 (FL-Tg) or a mutant CTLA-4 lacking the cytoplasmic region (truncated, TR-Tg), and analyzed thymocyte development. TR-T,cells express much higher CTLA-4 on the cell surface than FL-T,cells, in which most CTLA-4 was localized in intracellular vesicles. While CTLA-4,/, mice exhibit lymphoproliferative disease, neither of the Tg mice with CTLA-4,/, background developed the disorder. Although the development of thymocytes appeared normal in both Tg mice, in vivo depletion of double-positive thymocytes by injection of anti-CD3 Ab as well as the elimination of minor lymphocyte-stimulating antigen-reactive thymocytes were impaired in FL-Tg mice but not in TR-Tg mice. Functionally, cross-linking of CTLA-4 on thymocytes from FL-Tg mice, but not from TR-Tg mice, inhibited proliferation. These results reveal a potential role of CTLA-4, through its cytoplasmic domain, in the negative selection of thymocytes and in the prevention of lymphoproliferative disease. [source] PD-1 signalling in CD4+ T cells restrains their clonal expansion to an immunogenic stimulus, but is not critically required for peptide-induced toleranceIMMUNOLOGY, Issue 1 2010Joanne E. Konkel Summary The ultimate outcome of T-cell recognition of peptide,major histocompatibility complex (MHC) complexes is determined by the molecular context in which antigen presentation is provided. The paradigm is that, after exposure to peptides presented by steady-state dendritic cells (DCs), inhibitory signals dominate, leading to the deletion and/or functional inactivation of antigen-reactive T cells. This has been utilized in a variety of models providing peptide antigen in soluble form in the absence of adjuvant. A co-inhibitory molecule of considerable current interest is PD-1. Here we show that there is the opportunity for the PD-1/PD-L1 interaction to function in inhibiting the T-cell response during tolerance induction. Using traceable CD4+ T-cell receptor (TCR) transgenic cells, together with a blocking antibody to disrupt PD-1 signalling, we explored the roles of PD-1 in the induction of tolerance versus a productive immune response. Intact PD-1 signalling played a role in limiting the extent of CD4+ T-cell accumulation in response to an immunogenic stimulus. However, PD-1 signalling was not required for either the induction, or the maintenance, of peptide-induced tolerance; a conclusion underlined by successful tolerance induction in TCR transgenic cells genetically deficient for PD-1. These observations contrast with the reported requirement for PD-1 signals in CD8+ T-cell tolerance. [source] Role of protein kinase C-dependent A-kinase anchoring proteins in lysophosphatidic acid-induced cAMP signaling in human diploid fibroblastsAGING CELL, Issue 6 2006Ji-Heon Rhim Summary Previously, we reported that lysophosphatidic acid (LPA)-induced adenosine 3,,5,-cyclic monophosphate (cAMP) production by human diploid fibroblasts depends on the age of the fibroblasts. In this study, we examined the role of A-kinase anchoring proteins (AKAP) in the regulation of LPA-stimulated cAMP production in senescent fibroblasts. We found that levels of protein kinase C (PKC)-dependent AKAPs, such as Gravin and AKAP79, were elevated in senescent cells. Co-immunoprecipitation experiments revealed that Gravin and AKAP79 do not associate with adenylyl cyclase type 2 (AC2) but bind to AC4/6, which interacts with calcium-dependent PKCs ,/, both in young and senescent fibroblasts. When the expression of Gravin and AKAP79 was blocked by small interference RNA transfection, the basal level of cAMP was greatly reduced and the cAMP status after LPA treatment was also reversed. Protein kinase A showed a similar pattern in terms of its basal activity and LPA-dependent modulation. These data suggest that Gravin and to a lesser extent, AKAP79, may play important roles in maintaining the basal AC activity and in coupling the AC systems to inhibitory signals such as Gi, in young cells, and to stimulatory signals such as PKCs in senescent cells. This study also demonstrates that Gravin is especially important for the long-term activation of PKC by LPA in senescent cells. We conclude that LPA-dependent increased level of cAMP in senescent human diploid fibroblasts is associated with increases in Gravin levels resulting in its increased binding with and activation of calcium-dependent PKC ,/, and AC4/6. [source] Impact of changes in antigen level on CD38/PD-1 co-expression on HIV-specific CD8 T cells in chronic, untreated HIV-1 infection,,JOURNAL OF MEDICAL VIROLOGY, Issue 3 2010Thomas Vollbrecht Abstract Excessive immune activation is a hallmark of chronic uncontrolled HIV infection. During the past years, growing evidence suggests that immune inhibitory signals also play an important role in progressive disease. However, the relationship between positive and negative immune signals on HIV-specific CD8 T cells has not been studied in detail so far in chronic HIV-1 infection. In this study, the expression of markers of positive (CD38) and negative (PD-1) immune signals on virus-specific CD8 T cells in chronic, untreated HIV-1 infection was evaluated using intracellular cytokine staining. Viral escape mutations were assessed by autologous virus sequence analysis and subsequent peptide titration assays. Single-epitope CD8 T-cell responses toward Gag, Pol, and Nef were compared in 12 HIV-1 controllers (viral load <5,000,cp/ml) and 12 HIV-1 progressors (viral load >50,000,cp/ml) and a highly significant increase of CD38/PD-1 co-expression on virus-specific CD8 T cells in progressors was found (P,<,0.0001). The level of CD38/PD-1 co-expression was independent of epitope specificity. Longitudinal follow-up revealed a clear drop in CD38/PD-1 co-expression on virus-specific CD8 T cells after the suppression of antigen following either viral escape mutation or the initiation of HAART (P,=,0.004). Antigen persistence with a fluctuating viral load revealed stable levels of CD38/PD-1 co-expression whereas significant rises in viral load were accompanied or even preceded by substantial increases in CD38/PD-1 co-expression. The CD38/PD-1 phenotype clearly distinguishes HIV-specific CD8 T-cell responses between controllers and progressors. Whether it plays a causative role in disease progression remains debatable. J. Med. Virol. 82:358,370, 2010. © 2010 Wiley-Liss, Inc. [source] Dorsally derived BMP4 inhibits the induction of spinal cord oligodendrocyte precursorsJOURNAL OF NEUROCHEMISTRY, Issue 2002R. H. Miller During development oligodendrocyte precursors arise in a distinct domain of the ventral ventricular zone in the spinal cord that they share with motor neurons. The localized appearance of oligodendrocyte and motor neuron precursors is the result of local inductive signals including sonic hedgehog (Shh). Previous studies suggested that inhibitory signals from dorsal spinal cord act to sharpen the boundaries of the Shh induced region. Here we show that the dorsal spinal cord contains BMP4 during the developmental period when oligodendrocyte precursors first appear. In dissociated cultures of embryonic spinal cord cells, BMP4 competitively blocks the induction of oligodendrocyte precursors by Shh. Similarly, in embryonic slice preparations addition of BMP4 inhibited the appearance of oligodendrocyte precursors in the ventral spinal cord while addition of Shh enhanced their appearance. In vivo, transplantation of a BMP4 coated bead adjacent to the dorsal spinal cord inhibited ventral oligodendrogenesis while transplantation of a Shh coated bead enhanced ventral oligodendrogenesis. These data suggest that the initial localization of oligodendrocytes in the ventral spinal cord reflects the neutralization of dorsally-derived BMP4 inhibition by locally supplied Shh. [source] Interferon-, and Donor MHC Class I Control Alternative Macrophage Activation and Activin Expression in Rejecting Kidney Allografts: A Shift in the Th1-Th2 ParadigmAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2008K. S. Famulski Organ allografts deficient in interferon-, (Ifng) or major histocompatibility complex (MHC) class I products develop accelerated necrosis when rejection develops, depending on perforin and granzymes. Thus Ifng-induced donor class I products deliver inhibitory signals to host inflammatory cells. We used microarrays to investigate whether Ifng-induced donor class I products also control inflammation patterns in mouse kidney allografts. Compared to wild-type (WT) allografts, many transcripts were increased in both Ifng-deficient allografts (Ifng-suppressed transcripts [GSTs]) and class I-deficient allografts (class I-suppressed transcripts [CISTs]), with 73% overlap between GSTs and CISTs. Some GSTs and CISTs reflected increased necrosis, including known injury-induced transcripts. However, many GSTs and CISTs were independent of perforin, granzymes and necrosis, and were associated with alternative macrophage activation (AMA) (e.g. arginase I [Arg1], macrophage elastase [Mmp12] and macrophage mannose receptor 1 [Mrc1]). AMA transcripts were induced despite absence of host interleukin (IL)4 and IL13 receptors. The AMA inducer may be activins, whose genes (inhibin A [InhbA] and inhibin B [InhbB]) were increased in all allografts with AMA. We conclude that in allograft rejection, Ifng acts via donor Ifng receptors (Ifngr) to induce donor class Ia and Ib products, which engage host inflammatory cells to limit perforin-granzyme-mediated damage and prevent AMA associated with inhibition of activin expression. Thus, Ifng may control T helper type 2 (Th2) cell inflammation by induction of class I products. [source] Regulation of TGF-, signaling and its roles in progression of tumorsCANCER SCIENCE, Issue 3 2003Kohei Miyazono Transforming growth factor-, (TGF-,) is a potent growth inhibitor of most types of cells; therefore, perturbations of TGF-, signaling are believed to result in progression of various tumors. On the other hand, TGF-, has been shown to act as an oncogenic cyto-kine through induction of extracellular matrices, angiogenesis, and immune suppression. A wide variety of effects of TGF-p are mediated by physical interaction of signal transducer Smad proteins with various transcription factors. Among these, Runx3 plays a pivotal role in prevention of gastric cancer. TGF-, signaling is regulated by various mechanisms in the cytoplasm and nucleus. Inhibitory Smads (l-Smads) repress TGF-, signaling mainly by interacting with activated TGF-, receptors. Smad ubiquitin regulatory factors (Smurfs) play important roles in facilitating the inhibitory signals induced by l-Smads. In addition, the transcrip-tional co-repressors c-Ski and SnoN interact with Smads, and repress transcription induced by TGF-,. Abnormalities of these regulators of TGF-, signaling may thus participate in the progression of various tumors. (Cancer Sci 2003; 94: 230,234) [source] | |||||||||||||