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Mechanisms and functions for the duration of intercellular contacts made by lymphocytes

Key Points

  • The central paradigm by which intercellular contact times are controlled for priming and developing an immune response is the dynamic regulation of integrin-mediated adhesiveness.

  • Whether or not chemokine receptor activation promotes or destabilizes intercellular contacts could be influenced by where on the cell chemokine receptor ligation occurs.

  • One mechanism by which the balance of activating and inhibitory signals could determine an appropriate response is by the regulation of the duration of intercellular contacts.

  • The principle of kinetic proofreading can operate at the level of intercellular contacts such that for effector function to be realized, the duration of intercellular contacts must persist long enough to allow each step in the cellular process to be completed.

  • Dynamic behaviour of the cell surface membrane can greatly influence the duration of intercellular contacts through various specific processes.

  • There is substantial evidence, both in vitro and in vivo, that various effector cell functions are directly regulated by the duration of intercellular contacts.

  • The same processes that regulate intercellular contact times between lymphocytes can be usurped by viruses to aid their own transmission.

Abstract

Communication across intercellular contacts is central to establishing appropriate innate and adaptive immune responses. Recent imaging of lymphocyte interactions suggests that a complex orchestration of cell–cell contact times is a key correlate to establishing appropriate immune responses. Here I review the molecular and cellular processes that influence the duration of intercellular contacts, including integrin activation and dynamic changes in membrane morphology. I discuss how these processes can be regulated, for example, by the balance of activating and inhibitory receptor signals, and how they can establish the appropriate outcome for individual cell–cell interactions.

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Figure 1: The lymphocyte contact cycle.
Figure 2: Mechanisms to augment or reduce the duration of lymphocyte contacts.
Figure 3: Several membranous processes influence the duration of intercellular contacts.
Figure 4: Intercellular contact between a human natural killer cell and a target cell.

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Acknowledgements

I am grateful to members of my laboratory and M. Dustin for influential discussions. I thank N. Powell for help in preparation of illustrations. I apologize to the many scientists whose work I have not directly cited owing to space constraints. Research in my own laboratory is funded by the Medical Research Council, the Biotechnology and Biological Science Research Council, the Wellcome Trust and a Wolfson Royal Society Research Merit Award.

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Glossary

Outside-in signalling

The process by which ligation of a cell surface receptor activates signalling pathways inside the cell.

Immunological synapse

A large structured interface that forms at immune cell contacts where molecules required for adhesion and signalling accumulate.

Inside-out signal

A signal which activates intracellular signalling pathways that result in the activation of a cell surface receptor, such as integrins.

Fluorescence resonance energy transfer

(FRET). A quantum mechanical process by which excitation energy is transferred, without the emission of a photon, from a donor fluorochrome to an acceptor fluorochrome that is in close proximity. FRET can be used to determine intermolecular or intramolecular distances (in the range of 10–100 Å).

Microcluster

A discrete collection of molecules at the immunological synapse that can move in the plasma membrane and generate signals. They are smaller than supramolecular activation clusters, which can represent aggregates of multiple microclusters.

Filopodium

A slender cytoplasmic projection, which extends from the leading edge of migrating cells.

Natural killer group 2, member D

(NKG2D). A primary activation receptor encoded by the NK cell gene complex and expressed by all mature NK cells. It recognizes distinct families of ligands that are generally expressed only by infected, stressed or transformed cells.

Inhibitory immunological synapse

The site of immune cell contact where proteins segregate into micrometre scale domains and where directed signalling serves to terminate or prevent cell activation.

Non-obese diabetic mice

Mice that spontaneously develop a form of autoimmunity that closely resembles human type 1 diabetes.

Virological synapse

A structured intercellular contact where viral receptors and adhesive proteins accumulate to aid cell–cell transmission of a virus.

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Davis, D. Mechanisms and functions for the duration of intercellular contacts made by lymphocytes. Nat Rev Immunol 9, 543–555 (2009). https://doi.org/10.1038/nri2602

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