Article

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

ABSTRACT

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 is most evident during CD4 + T cell activation, a process that involves major rearrangements of the T cell proteome and lipidome [8] [9]. Engagement of the TCR with an antigen peptide displayed by MHCII of an APC results in the formation of a higher ordered structure termed the immunological synapse (IS) [8] [9] [10]. Signaling at the IS is highly coordinated through the temporally ordered recruitment of signaling-propagating, and exclusion of signaling-terminating, proteins [11] [12]. "
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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.
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