New insights into the t cell synapse from single molecule techniques. Nat Rev Immunol

Helene and Martin Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, 540 First Avenue, New York, New York 10012, USA.
Nature Reviews Immunology (Impact Factor: 34.99). 09/2011; 11(10):672-84. DOI: 10.1038/nri3066
Source: PubMed


T cell activation depends on extracellular ligation of the T cell receptor (TCR) by peptide-MHC complexes in a synapse between the T cell and an antigen-presenting cell. The process then requires the assembly of signalling complexes between the TCR and the adaptor protein linker for activation of T cells (LAT), and subsequent filamentous actin (F-actin)-dependent TCR cluster formation. Recent progress in each of these areas, made possible by the emergence of new techniques, has forced us to rethink our assumptions and consider some radical new models. These describe the receptor interaction parameters that control T cell responses and the mechanism by which LAT is recruited to the TCR signalling machinery. This is an exciting time in T cell biology, and further innovation in imaging and genomics is likely to lead to a greater understanding of how T cells are activated.

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    • "This whole process of antigen capture and presentation, together with T and B lymphocyte activation schematised here is a complex process that involves various types of DCs and macrophages that cooperate to mount innate and adaptive immune responses. A common feature of immunological synapses is the T (B, NK) cell polarisation towards the APC, manifested as cytoskeletal (actin and microtubules) reorganisation, intracellular vesicle traffic and molecular clustering of receptors and signalling molecules at the cell–cell contact site (Figure 2) (Dustin and Depoil, 2011; Harwood and Batista, 2010; Lagrue et al., 2013; Mace et al., 2014; Soares et al., 2013b). "
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    • "Three SMACs have been described, which are named central SMAC (cSMAC), peripheral SMAC (pSMAC), and distal SMAC (dSMAC), according to their relative localization in the cell interface (Fig. 3). The cSMAC contains the TCR/CD3 complex, whereas the pSMAC has a high content of lymphocyte function-associated antigen 1 (LFA-1), and the dSMAC harbors receptors with large extracellular domains like CD45 (reviewed in 1–61). Notably, both costimulation and sustained actin dynamics are important to build and maintain a mature immune synapse 4–65. "
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    ABSTRACT: Cofilin is an actin-binding protein that depolymerizes and/or severs actin filaments. This dual function of cofilin makes it one of the major regulators of actin dynamics important for T-cell activation and migration. The activity of cofilin is spatio-temporally regulated. Its main control mechanisms comprise a molecular toolbox of phospho-, phospholipid, and redox regulation. Phosphorylated cofilin is inactive and represents the dominant cofilin fraction in the cytoplasm of resting human T cells. A fraction of dephosphorylated cofilin is kept inactive at the plasma membrane by binding to phosphatidylinositol 4,5-bisphosphate. Costimulation via the T-cell receptor/CD3 complex (signal 1) together with accessory receptors (signal 2) or triggering through the chemokine SDF1α (stromal cell-derived factor 1α) induce Ras-dependent dephosphorylation of cofilin, which is important for immune synapse formation, T-cell activation, and T-cell migration. Recently, it became evident that cofilin is also highly sensitive for microenvironmental changes, particularly for alterations in the redox milieu. Cofilin is inactivated by oxidation, provoking T-cell hyporesponsiveness or necrotic-like programmed cell death. In contrast, in a reducing environment, even phosphatidylinositol 4,5-bisphosphate -bound cofilin becomes active, leading to actin dynamics in the vicinity of the plasma membrane. In addition to the well-established three signals for T-cell activation, this microenvironmental control of cofilin delivers a modulating signal for T-cell-dependent immune reactions. This fourth modulating signal highly impacts both initial T-cell activation and the effector phase of T-cell-mediated immune responses.
    Immunological Reviews 11/2013; 256(1):30-47. DOI:10.1111/imr.12115 · 10.12 Impact Factor
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    • "Monocyte-derived DCs (moDCs) with inflammatory properties have recently been validated as functionally competent cDCs, which can be generated in vivo under inflammatory conditions [9] and in vitro in the presence of specific cytokines [10]. moDCs continuously sense, internalize and process protein antigens and present their degradation products to naive T-lymphocytes with concomitant co-stimulatory signals that drive T-cell activation and differentiation to effector cells with different functional attributes [11]. "
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    ABSTRACT: The aim of this study was to characterize and identify the mode of action of IC31®, a two-component vaccine adjuvant. We found that IC31® was accumulated in human peripheral blood monocytes, MHC class II positive cells and monocyte-derived DCs (moDCs) but not in plasmacytoid DCs (pDCs). In the presence of IC31® the differentiation of inflammatory CD1a(+) moDCs and the secretion of chemokines, TNF-α and IL-6 cytokines was inhibited but the production of IFNβ was increased. Sustained addition of IC31® to differentiating moDCs interfered with IκBα phosphorylation, while the level of phospho-IRF3 increased. We also showed that both IC31® and its KLK component exhibited a booster effect on type I IFN responses induced by the specific ligands of TLR3 or TLR7/8, whereas TLR9 ligand induces type I IFN production only in the presence of IC31® or ODN1. Furthermore, long term incubation of moDCs with IC31® caused significantly higher expression of IRF and IFN genes than a single 24 hr treatment. The adjuvant activity of IC31® on the IFN response was shown to be exerted through TLRs residing in the vesicular compartment of moDCs. Based on these results IC31® was identified as a moDC modulatory adjuvant that sets the balance of the NF-κB and IRF3 mediated signaling pathways to the production of IFNβ. Thus IC31® is emerging as a potent adjuvant to increase immune responses against intracellular pathogens and cancer in future vaccination strategies.
    PLoS ONE 10/2013; 8(2):e55264. DOI:10.1371/journal.pone.0055264 · 3.23 Impact Factor
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