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Activation Events (activation + event)
Selected AbstractsInitiation of TCR signaling: regulation within CD3 dimersIMMUNOLOGICAL REVIEWS, Issue 1 2003Balbino Alarcón Summary: The number of possible T cell activation outcomes resulting from T cell receptor (TCR) engagement suggests that the TCR is able to differentially activate a myriad of signaling pathways depending on the nature of the stimulus. The complex structural organization of the TCR itself could underlie this diversity of responses. Assembly and stoichiometric studies have helped us to shed some light on the initiation of TCR signaling. The TCR is composed of TCR and CD3 dimers. Changes in the interaction between CD3 subunits within the CD3 dimers and in the interaction of these dimers with the TCR heterodimer could be the triggering mechanism that initiates the first activation events. One of the hallmarks of these early changes in TCR conformation is the induced recruitment of the adapter protein Nck to a proline-rich sequence of the cytoplasmic tail of CD3,, but there may be others. According to our most recent observations, the TCR is organized in pre-existing clusters within plasma membrane microdomains, exhibiting a complexity above and beyond that of dimer composition complexity. How the presence of TCR in clusters influences TCR avidity and propagation of TCR signals is something that has yet to be investigated. [source] Mechanisms of regulatory T-cell suppression , a diverse arsenal for a moving targetIMMUNOLOGY, Issue 1 2008Dorothy K. Sojka Summary Naturally-occurring regulatory T cells (Tregs) are emerging as key regulators of immune responses to self-tissues and infectious agents. Insight has been gained into the cell types and the cellular events that are regulated by Tregs. Indeed, Tregs have been implicated in the control of initial activation events, proliferation, differentiation and effector function. However, the mechanisms by which Tregs disable their cellular targets are not well understood. Here we review recent advances in the identification of distinct mechanisms of Treg action and of signals that enable cellular targets to escape regulation. Roles for inhibitory cytokines, cytotoxic molecules, modulators of cAMP and cytokine competition have all been demonstrated. The growing number of inhibitory mechanisms ascribed to Tregs suggests that Tregs take a multi-pronged approach to immune regulation. It is likely that the relative importance of each inhibitory mechanism is context dependent and modulated by the inflammatory milieu and the magnitude of the immune response. In addition, the target cell may be differentially susceptible or resistant to distinct Treg mechanisms depending on their activation or functional status at the time of the Treg encounter. Understanding when and where each suppressive tool is most effective will help to fine tune therapeutic strategies to promote or constrain specific arms of Treg suppression. [source] Chemokine Signaling to Lymphocyte Integrins Under Shear FlowMICROCIRCULATION, Issue 1 2009RONEN ALON ABSTRACT The arrest of lymphocytes at target vascular sites depends on the rapid activation of their integrins by specialized endothelial chemokines. For over a decade, the mechanisms by which these chemokines trigger initial integrin-mediated adhesiveness and subsequent adhesion strengthening and crawling over endothelial surfaces have been dissected in vitro using flow chamber setups. These studies revealed that lymph node chemokines and subsets of inflammatory chemokines, collectively termed "arrest chemokines," can trigger the fastest measurable inside-out integrin activation events. Recent studies indicate that shear forces applied on lymphocytes are instrumental in these rapid activation processes. Different GTPases have been implicated in these activation processes. As these enzymes contribute to successive integrin activation and redistribution processes in both early and prolonged contacts there is a growing need to dissect in vitro and validate in vivo specific signaling routes involved in early and late integrin activation events controlling lymphocyte arrest and their subsequent crawling to sites of diapedesis. In this article, we present an overview of both early and recent shear-flow studies of integrin activation in lymphocytes and discuss future perspectives of integrin activation research in vitro and in vivo. [source] Signaling satellite-cell activation in skeletal muscle: Markers, models, stretch, and potential alternate pathwaysMUSCLE AND NERVE, Issue 3 2005Ashley C. Wozniak BSc Abstract Activation of skeletal muscle satellite cells, defined as entry to the cell cycle from a quiescent state, is essential for normal growth and for regeneration of tissue damaged by injury or disease. This review focuses on early events of activation by signaling through nitric oxide and hepatocyte growth factor, and by mechanical stimuli. The impact of various model systems used to study activation and the regulation of satellite-cell quiescence are placed in the context of activation events in other tissues, concluding with a speculative model of alternate pathways signaling satellite-cell activation. Muscle Nerve, 2005 [source] Ex vivo Inhibition of NF-,B Signaling in Alloreactive T-cells Prevents Graft-Versus-Host DiseaseAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009M. J. O'Shaughnessy The ex vivo induction of alloantigen-specific hyporesponsiveness by costimulatory pathway blockade or exposure to immunoregulatory cytokines has been shown to inhibit proliferation, IL-2 production, and the graft-versus-host disease (GVHD) capacity of adoptively transferred T-cells. We hypothesized that inhibition of the intracellular NF-,B pathway in alloreactive T-cells, which is critical for T-cell activation events including IL-2 transcription, could lead to alloantigen hyporesponsiveness and loss of GVHD capacity. We demonstrate that treatment of mixed lymphocyte reaction (MLR) cultures with PS1145, a potent inhibitor of NF-,B activation, can induce T-cell hyporesponsiveness to alloantigen in primary and secondary responses while preserving in vitro responses to potent mitogenic stimulation. GVHD lethality in recipients of ex vivo PS1145-treated cells was profoundly inhibited. Parking of control or PS1145-treated MLR cells in syngeneic Rag,/, recipients resulted in intact contact hypersensitivity (CHS) responses. However, GVHD lethality capacity also was restored, suggesting that lymphopenic expansion uncoupled alloantigen hyporesponsiveness. These results indicate that the NF-,B pathway is a critical regulator of alloresponses and provide a novel small molecule inhibitor based approach that is effective in preventing early posttransplant GVHD lethality but that also permits donor T-cell responses to recover after a period of lymphopenic expansion. [source] | ||||||||||