The immunological synapse.

Abstract

What is it? The immunological synapse is an area of close membrane apposition observed during the interaction between a presenting cell bearing a specific antigen and a T lymphocyte.Why is it important? The synapse is thought to be the type of intercellular contact through which antigenic peptides — bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs) — are recognized by the antigen receptors on T lymphocytes. This binding leads to intracellular signals that are critical for lymphocyte activation. It is thought to be essential for effective recognition of surface-bound antigen.How does it form? First, the recruitment into the contact zone of some adhesion molecules such as CD2 and LFA-1 helps to bring the membrane bilayers of the two interacting cells together. This facilitates the interactions of the T-cell receptor (TCR) with its ligand, neither of which extend very far from the membrane surface. Second, this high density of molecules may help overcome the intrinsic weak affinity of the TCR for the small number of specific MHC—peptide complexes usually borne by APCs.What is it made of? Many molecules expressed in T lymphocytes or in APCs accumulate in the area of the synapse. There are some integral membrane proteins (such as the TCR, MHC molecules, CD3-ϵ, CD4, CD2, LFA-1, ICAM-1, CD48, CDS8 and CD45), some cytoskeletal proteins (talin and CD2-associated protein) and some signaling molecules (PKC-θ, Lck, Fyn and MEKK2).Are the molecules homogeneously distributed in the synapse? Surprisingly, no. Recent studies have shown that the molecules are arranged in two distinct microdomains; the synapse Consists of a central core surrounded by a ring (see FigureFigure). There is intriguing, but still incomplete, information about the segregation of some of the T-cell molecules within the synapse; for this reason, some proteins are not shown in the FigureFigure.Figure 1Cross-section of the immunological synapse 30 mm after the initial contact, showing the different molecules that partition in the synapse in two discrete areas — also called supramolecular activation clusters' (SMACs). The T-cell molecules TCR/CD3-g (dark blue), CD2 (purple) and PKC-9 (pink) are in the central SMAC (cSMAC), whereas LFA-1 (orange) and talin (red) are found in a concentric peripheral zone (pSMAC). The transmembrane molecules are illustrated in proportion to their actual molecular dimensions. Antigenic peptides bound to MHC molecules are coloured grey, CD48/CD58 molecules are coloured brown and ICAM-1 is coloured yellow.View Large Image | View Hi-Res Image | Download PowerPoint SlideSo, is everything important clustered into the synapse? It's true that most molecules known to be involved in TCR-dependent signalling are found in the synapse, so that immunologists now tend to ask of any particular molecule in which they are interested: ‘Tell me if you are in the synapse and I'll tell you if you are important for T-cell activation’. Nevertheless, it turns out that many proteins are not present in the synapse and, in some cases, only particular isoforms accumulate in the synapse. The only protein that has been shown to be specifically excluded from the synapse is CD43.How do proteins get moved to the synapse? The T-cell cytoskeleton —in particular, actin rnicrofilaments and myosin motors — is thought to have a key role in driving the redistribution of synapse molecules.What remains to be discovered? A lot. Imaging of GFP-tagged molecules is now being used to follow the redistribution of molecules in living cells. This provides both precise timing and spatial information. Interestingly, the architectural changes can be correlated with the intensity of T-cell activation through the measurement of the rise in intracellular calcium concentration that occurs within seconds after antigen recognition. With the development of new GFP variants and the possibility of transducing normal T lymphocytes using retroviruses, there's bound to be plenty more information soon.Where can I find out more?Brown MJ, Shaw S: T-cell activation: interplay at the interface. Curr Biol 1999, 9:R26-R28.Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML: The immunological synapse: a molecular machine controlling T cell activation.Science 1999, 285:221-227.Monks CRF, Freiberg BA, Kupfer H, Sciaky N, Kupfer A: Three-dimensional segregation of supramolecular activation clusters in T cells.Nature 1998, 395:82-86.Wulfing C, Davis MM: A receptor/cytoskeletal movement triggered by costimulation during T cell activation. Science 1998, 282:2266-2269.