Trends in Immunology
Volume 23, Issue 7, 1 July 2002, Pages 356-363
Journal home page for Trends in Immunology

Review
Assembly of the immunological synapse for T cells and NK cells

https://doi.org/10.1016/S1471-4906(02)02243-3Get rights and content

Abstract

Recent three-dimensional fluorescence imaging of immune surveillance by different lymphocytes indicates common processes in the assembly of immunological synapses. After proteins accumulate at intercellular contacts, they segregate into domains that can be subsequently organized. This is sometimes accompanied by signalling through lipid rafts before effector functions such as secretion. Segregation of some proteins can be spontaneous, such as at the inhibitory natural killer (NK) cell synapse, but protein clustering and organization can also be controlled by ATP-dependent cytoskeletal movements, such as during full T-cell activation. A complete understanding of the supramolecular chemistry at immunological synapses in living cells requires the application of new technologies such as fluorescence lifetime imaging.

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)

  • J. Delon

    Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin

    Immunity

    (2001)
  • R.D. Klausner

    Lipid domains in membranes. Evidence derived from structural perturbations induced by free fatty acids and lifetime heterogeneity analysis

    J. Biol. Chem.

    (1980)
  • D.A. Brown et al.

    Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface

    Cell

    (1992)
  • F. Balamuth

    Distinct patterns of membrane microdomain partitioning in Th1 and Th2 cells

    Immunity

    (2001)
  • L.A. Bagatolli

    Water dynamics in glycosphingolipid aggregates studied by laurdan fluorescence

    Biophys. J.

    (1998)
  • P. Schwille

    Molecular dynamics in living cells observed by fluorescence correlation spectroscopy with one- and two-photon excitation

    Biophys. J.

    (1999)
  • M.L. Dustin

    Environmental control of immunological synapse formation and duration

    Trends Immunol.

    (2001)
  • M. Gunzer

    Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential

    Immunity

    (2000)
  • P. Friedl et al.

    Interaction of T cells with APCs: the serial encounter model

    Trends Immunol.

    (2001)
  • D.N. Burshtyn

    Adhesion to target cells is disrupted by the killer cell inhibitory receptor

    Curr. Biol.

    (2000)
  • C.R. Monks

    Three-dimensional segregation of supramolecular activation clusters in T cells

    Nature

    (1998)
  • A. Grakoui

    The immunological synapse: a molecular machine controlling T cell activation

    Science

    (1999)
  • D.M. Davis

    The human natural killer cell immune synapse

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • M.L. Dustin et al.

    The immunological synapse and the actin cytoskeleton: molecular hardware for T cell signaling

    Nat. Immunol.

    (2000)
  • M.L. Dustin

    Identification of self through two-dimensional chemistry and synapses

    Annu. Rev. Cell Dev. Biol.

    (2001)
  • E. Donnadieu

    Imaging T-cell antigen recognition and comparing immunological and neuronal synapses

    Immunology

    (2001)
  • D.M. Davis

    Molecular recognition of disease at natural killer cell immune synapses

    Sci. Prog.

    (2000)
  • S.K. Bromley

    The immunological synapse

    Annu. Rev. Immunol.

    (2001)
  • M.A. McCloskey et al.

    Contact-induced redistribution of specific membrane components: local accumulation and development of adhesion

    J. Cell Biol.

    (1986)
  • A. Kupfer et al.

    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.

    (1989)
  • C. Wülfing et al.

    A receptor/cytoskeletal movement triggered by costimulation during T cell activation

    Science

    (1998)
  • C. Wülfing

    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.

    (1998)
  • C. Gomez-Mouton

    Segregation of leading-edge and uropod components into specific lipid rafts during T cell polarization

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • H. Kropshofer

    Tetraspan microdomains distinct from lipid rafts enrich select peptide–MHC class II complexes

    Nat. Immunol.

    (2002)
  • S. Hakomori

    The glycosynapse

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • A. Delaguillaumie

    Rho GTPases link cytoskeletal rearrangements and activation processes induced via the tetraspanin CD82 in T lymphocytes

    J. Cell Sci.

    (2002)
  • C. Wülfing

    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.

    (2000)
  • C. Wülfing

    Costimulation and endogenous MHC ligands contribute to T cell recognition

    Nat. Immunol.

    (2002)
  • A.D. Holdorf

    Regulation of Lck activity by CD4 and CD28 in the immunological synapse

    Nat. Immunol.

    (2002)
  • L.M. Carlin

    Intercellular transfer and supramolecular organization of human leukocyte antigen C at inhibitory natural killer cell immune synapses

    J. Exp. Med.

    (2001)
  • P.C. Cheng

    Translocation of the B cell antigen receptor into lipid rafts reveals a novel step in signaling

    J. Immunol.

    (2001)
  • J.H. Phillips

    Superantigen-dependent, cell-mediated cytotoxicity inhibited by MHC class I receptors on T lymphocytes

    Science

    (1995)
  • M.M. Al-Alwan

    The dendritic cell cytoskeleton is critical for the formation of the immunological synapse

    J. Immunol.

    (2001)
  • Cited by (116)

    • Sterol Regulation of Voltage-Gated K<sup>+</sup> Channels

      2017, Current Topics in Membranes
      Citation 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 Immunity
    • Mechanisms for size-dependent protein segregation at immune synapses assessed with molecular rulers

      2011, Biophysical Journal
      Citation 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
    View all citing articles on Scopus
    View full text