Trends in Immunology
ReviewAssembly of the immunological synapse for T cells and NK cells
Section snippets
Defining the IS
There has been some flexibility in the use of the term IS in the current literature. Here, it is suggested that an IS be defined as an intercellular contact, involving at least one cell of the immune system, at which the encounter causes proteins to segregate into micrometer-scale domains. Other definitions have been suggested, such as any intercellular contact involving an immune cell, but this leads to the problem of defining how long or how tightly cells should be clasped together before it
Stage 1: accumulation of proteins at the intercellular contact
Accumulation of cognate ligands and receptors occurs at intercellular contacts 12., 13., as first observed in living cells by Wülfing and Davis 14., 15.. It is unclear whether or not this accumulation of protein at intercellular contacts is related to the extensive earlier studies of protein capping induced by soluble antibodies.
Even before cells meet, an intrinsic polarization in the distribution of some proteins probably exists in each cell. However, the extent to which such cellular
Signalling by lipid rafts at the IS
A considerable amount of research has focused on a possible relationship between the IS and lipid rafts. Lipid rafts are dynamic domains of the cell surface enriched with glycosphingolipids and cholesterol, postulated to be in a liquid-ordered phase within the bulk liquid-disordered phospholipid bilayer [49]. Heterogeneity in the cell-surface membrane was identified by heterogeneity in the nanosecond fluorescence lifetime of diphenylhexatriene (DPH) in purified lymphocyte membranes [50].
Intercellular transfer of cell-surface proteins at the IS
At the T-cell IS, cell-surface proteins of the target, including MHC protein and membrane fragments, transfer to T cells 35., 71., 72., 73. (recently reviewed in Ref. [74]). Furthermore, B cells have been shown to acquire antigen from APCs at a B-cell IS [68]. In both of these cases, it has been suggested that the transferred MHC protein, or B-cell antigen, is used to activate neighbouring T cells. However, inhibitory MHC class I protein also transfers from target cells to NK cells, both for
Imaging immune surveillance in the future: beyond simple description of the IS
Just as the structural arrangement of atoms is intimately related to the function of a protein molecule, so does the spatial organization of molecules in the IS facilitate the outcome of the intercellular communication. Until recently, this was a relatively unexplored perspective: the collective view of molecular immunology has tended to be dominated by the arrangement of atoms in proteins rather than the arrangement of molecules in cells. Indeed, techniques that have successfully driven
Concluding remarks
Like the neuronal synapse, the IS is diverse in structure and function, and the generalized model proposed here can serve to highlight the varied characteristics of each type of IS. The outcome of the formation of an IS could be affected by regulation at each stage in its assembly. For example, an extracellular matrix can regulate the engagement between cells 82., 83., 84. and chemokine gradients have the ability to both recruit and inhibit T cells [85]. Also, subsequent tight conjugation of
Acknowledgements
I thank A.I. Magee and B.A. Askonas for critically reading the manuscript and members of my laboratory for stimulating discussions. The anonymous reviews and the Editor's comments were also particularly useful. I thank D. Bacon for help with the figures. I apologize to scientists whose research I could not cite owing to space limitations. Research in my laboratory is funded by the MRC (UK) and the BBSRC (UK).
References (87)
Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition
Semin. Immunol.
(2000)- et al.
Information transfer at the immunological synapse
Curr. Biol.
(2000) - et al.
Dynamics of the immunological synapse: finding, establishing and solidifying a connection
Curr. Opin. Immunol.
(2002) Evaluation of prototype transmembrane 4 superfamily protein complexes and their relation to lipid rafts
J. Biol. Chem.
(2001)Vav1 controls integrin clustering and MHC/peptide-specific cell adhesion to antigen-presenting cells
Immunity
(2002)- et al.
Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength
Immunity
(2002) WIP deficiency reveals a differential role for WIP and the actin cytoskeleton in T and B cell activation
Immunity
(2002)The immunological synapse of CTL contains a secretory domain and membrane bridges
Immunity
(2001)ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse
Immunity
(2001)The membrane–microfilament linker ezrin is involved in the formation of the immunological synapse and in T cell activation
Immunity
(2001)
Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin
Immunity
Lipid domains in membranes. Evidence derived from structural perturbations induced by free fatty acids and lifetime heterogeneity analysis
J. Biol. Chem.
Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface
Cell
Distinct patterns of membrane microdomain partitioning in Th1 and Th2 cells
Immunity
Water dynamics in glycosphingolipid aggregates studied by laurdan fluorescence
Biophys. J.
Molecular dynamics in living cells observed by fluorescence correlation spectroscopy with one- and two-photon excitation
Biophys. J.
Environmental control of immunological synapse formation and duration
Trends Immunol.
Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential
Immunity
Interaction of T cells with APCs: the serial encounter model
Trends Immunol.
Adhesion to target cells is disrupted by the killer cell inhibitory receptor
Curr. Biol.
Three-dimensional segregation of supramolecular activation clusters in T cells
Nature
The immunological synapse: a molecular machine controlling T cell activation
Science
The human natural killer cell immune synapse
Proc. Natl. Acad. Sci. U. S. A.
The immunological synapse and the actin cytoskeleton: molecular hardware for T cell signaling
Nat. Immunol.
Identification of self through two-dimensional chemistry and synapses
Annu. Rev. Cell Dev. Biol.
Imaging T-cell antigen recognition and comparing immunological and neuronal synapses
Immunology
Molecular recognition of disease at natural killer cell immune synapses
Sci. Prog.
The immunological synapse
Annu. Rev. Immunol.
Contact-induced redistribution of specific membrane components: local accumulation and development of adhesion
J. Cell Biol.
The specific interaction of helper T cells and antigen-presenting B cells. IV. Membrane and cytoskeletal reorganizations in the bound T cell as a function of antigen dose
J. Exp. Med.
A receptor/cytoskeletal movement triggered by costimulation during T cell activation
Science
Visualizing the dynamics of T cell activation: intracellular adhesion molecule 1 migrates rapidly to the T cell/B cell interface and acts to sustain calcium levels
Proc. Natl. Acad. Sci. U. S. A.
Segregation of leading-edge and uropod components into specific lipid rafts during T cell polarization
Proc. Natl. Acad. Sci. U. S. A.
Tetraspan microdomains distinct from lipid rafts enrich select peptide–MHC class II complexes
Nat. Immunol.
The glycosynapse
Proc. Natl. Acad. Sci. U. S. A.
Rho GTPases link cytoskeletal rearrangements and activation processes induced via the tetraspanin CD82 in T lymphocytes
J. Cell Sci.
The vav exchange factor is an essential regulator in actin-dependent receptor translocation to the lymphocyte-antigen-presenting cell interface
Proc. Natl. Acad. Sci. U. S. A.
Costimulation and endogenous MHC ligands contribute to T cell recognition
Nat. Immunol.
Regulation of Lck activity by CD4 and CD28 in the immunological synapse
Nat. Immunol.
Intercellular transfer and supramolecular organization of human leukocyte antigen C at inhibitory natural killer cell immune synapses
J. Exp. Med.
Translocation of the B cell antigen receptor into lipid rafts reveals a novel step in signaling
J. Immunol.
Superantigen-dependent, cell-mediated cytotoxicity inhibited by MHC class I receptors on T lymphocytes
Science
The dendritic cell cytoskeleton is critical for the formation of the immunological synapse
J. Immunol.
Cited by (116)
Impact of different classification schemes on discrimination of proteins with noise-contaminated spectra using laboratory-measured fluorescence data
2023, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopySterol Regulation of Voltage-Gated K<sup>+</sup> Channels
2017, Current Topics in MembranesCitation Excerpt :This signaling platform is dynamically assembled upon presentation of the antigen to the T cell by professional APCs. The IS signaling platform contains TCR/CD3 complex along with the auxiliary, signal transducer and scaffolding proteins (extensively reviewed in Bromley et al., 2001; Davis, 2002; Dustin, 2014). Lipid rafts are found to accumulate at the IS, as was reported by staining the cells with cholera toxin B subunit (CTB), which binds to ganglioside M1 (GM1), a marker of raft membranes (Janes, Ley, & Magee, 1999; Janes, Ley, Magee, & Kabouridis, 2000; Viola, Schroeder, Sakakibara, & Lanzavecchia, 1999).
Natural Killer Cells
2013, Antibody Fc: Linking Adaptive and Innate ImmunityMechanisms for size-dependent protein segregation at immune synapses assessed with molecular rulers
2011, Biophysical JournalCitation Excerpt :Immune synapses are specialized cell-cell contacts involving many immune cell-types, including T cells, B cells, and natural killer (NK) cells. Immune synapses typically have an area of a few tens of square micrometers, and although their structure may vary (3,4), the prototypical mature or late-stage immune synapse has a concentric ring-shaped organization, where the immune receptor-ligand complexes which have short extracellular domains accumulate in the central region and the longer integrin complexes accumulate around this (1). The complexes of many immune cell receptors bound to their ligands on the target cell—such as complexes of T cell receptor with peptide-loaded major histocompatibility complex proteins (pMHC), Killer immunoglobulin-like receptors (KIR) with pMHC, and natural killer cell receptor D with MHC class I polypeptide-related sequence A—have an extracellular span of ∼10–15 nm whereas complexes formed by integrins have longer extracellular dimensions of ∼40 nm (1,5,6).
NK cell-mediated target cell death
2010, Natural Killer Cells