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T-cell-antigen recognition and the immunological synapse

Key Points

  • The original meaning of the Greek term 'synapse' is probably best described as 'connection' or 'junction' between two similar entities. We define the 'immunological synapse' as any stable, flattened interface between a lymphocyte or natural killer cell and a cell that they are in the process of recognizing.

  • Synapse formation is an energy-dependent process that causes a marked polarization of the T cell, involving cytoskeletal rearrangement, in particular the movement of the microtubule organizing centre (MTOC) from the rear end of the T cell to a location underneath the synapse.

  • The mature immunological synapse is best described between T helper cells and their conjugated antigen-presenting cells (APCs), where it is organized in distinct areas, known as supra-molecular activation complexes (SMACs). The central SMAC (cSMAC) is enriched in T-cell receptors (TCR) and many of its accessory polypeptides and signalling molecules. Cell adhesion seems to predominate in a peripheral ring that surrounds the cSMAC (pSMAC) and bulky molecules accumulate in a region distal to the synapse (dSMAC) — that is, outside of the pSMAC.

  • Co-stimulation, as provided through CD28–CD80/CD86 and leukocyte function-associated antigen 1 (LFA1)–intercellular adhesion molecule 1 (ICAM1) interactions, is required for molecular recruitment to the synapse, which is mediated through cytoskeletal mechanisms.

  • Agrin and MGAT5 have recently been described as genes that influence the degree of molecular segregation. The role of the size of the extracellular domain of synapse-localized membrane proteins in large-scale patterning is presently debated.

  • TCR-proximal signalling precedes the formation of the mature immunological synapse and is most marked before its formation, however, TCR-mediated signals do not only continue throughout the lifetime of the synapse but also actively maintain the synapse. Premature abrogation of later TCR signals markedly affects the response of the T cell.

  • Advances in imaging technology make it increasingly possible to study the dynamics of synapse formation in vivo (in lymph nodes, thymus, for example). At present, there is a debate over the duration of such interactions as they occur in the course of T-cell priming.

  • Although most studies deal with the synapse between effector T helper cells and B-cell tumour lines, the field is now moving towards more specialized scenarios. Considerable 'deviations from the rule' become increasingly evident and highlight the physiological and developmental context as well as location in the body in which antigenic information is conveyed through the immunological synapse.

  • With increasing research devoted to the immune synapse, its function is presently under scrutiny. A recent study describes it as a 'servo-controller' that boosts T-cell sensitivity and attenuates strong signals. In addition, we envision the immune synapse as a platform that provides sufficient regulatory mechanisms which are required to guide T-cell activity in accordance with its developmental stage, its range of functions, the nature of the APC involved, as well as both the quality and quantity of TCR ligands involved.

Abstract

Much excitement of the past five years in the area of T-cell-antigen recognition has centred around the immunological synapse — a complex cellular structure that forms at the interface of a T cell and a cell that expresses the appropriate peptide–MHC complexes. Thanks to new imaging technologies, we are now beginning to understand the role of cell-surface molecules and some of their attendant signalling modules in the context of cell-to-cell communication. Progress has been so rapid that T-cell-antigen recognition might be the first system in which the molecular basis of cell–cell recognition is understood.

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Figure 1: Overview of a mature T-cell synapse.
Figure 2: T-cell sensitivity and synapse initiation.
Figure 3: Morphological and cytoskeletal changes in the initial engagement and formation of a stable T-helper-cell synapse.
Figure 4: Signalling in the immunological synapse.
Figure 5: Comparison between synapse formation in CD4+ T helper cells and cytotoxic T lymphocytes (CTLs).

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Acknowledgements

We thank all members of the Davis and Chien Laboratory for thoughtful discussions and for maintaining a truly synergistic working environment. Work is supported by the Howard Hughes Medical Institute and the National Institutes of Health.

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Correspondence to Mark M. Davis.

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DATABASES

LocusLink

Agrin

CD2

Cd2ap

CD28

CD43

CD45

CD48

CTLA4

ICAM1

LFA1

MGAT5

NFAT

PKC-θ

SHP2

talin

Further information

Alliance for cellular signalling

Confocal microscopy

Glossary

CHARGE COUPLED DEVICE

(CCD). A slab of silicon semiconductor that is divided into an array of pixels that function as photodiodes and a light-sensitive photodetector.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). An imaging technique to analyse intermolecular distances based on the transfer of energy from a donor molecule to an acceptor molecule without the emission of a photon.

TOTAL INTERNAL REFLECTION FLUORESCENCE MICROSCOPY

(TIRFM). TIRFM is used to observe molecule fluorescence that is restricted to surfaces and interfaces and, therefore, is increasingly used to investigate the interaction of molecules with surfaces.

LIPID RAFTS

Specialized membrane domains in the plasma membrane that are enriched in a subset of glycolipids, cholesterol and certain proteins containing either a particular transmembrane domain or which are post-translationally modified with saturated acyl chains. Their exact properties (size, existence of sub species) and function in living cells is debated.

FLUORESCENCE RECOVERY AFTER PHOTOBLEACHING

(FRAP). The diffusion coefficient and the mobile fraction of the detected species can be determined by FRAP where a small region is irreversibly bleached once with a short, intense laser pulse and the subsequent kinetics of the fluorescence recovery in the same bleached volume is recorded.

EZRIN–RADIXIN–MOESIN (ERM) FAMILY

The ERM family consists of three closely related proteins ezrin, radixin and moesin, which provide a regulated linkage between the cortical actin cytoskeleton and certain transmembrane proteins in the plasma membrane. There is increasing evidence that ERM family proteins participate in signal transduction.

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Huppa, J., Davis, M. T-cell-antigen recognition and the immunological synapse. Nat Rev Immunol 3, 973–983 (2003). https://doi.org/10.1038/nri1245

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