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Origins of the cytolytic synapse

Nature Reviews Immunology volume 16, pages 421–432 (2016)Cite this article

Subjects

Key Points

  • Ordering the events that lead to the formation of the cytolytic synapse provides a better understanding of the molecular mechanisms that are involved.

  • The reorganization of both actin and microtubule cytoskeletons has key roles in polarizing secretion at the cytolytic synapse.

  • The immune synapse and the primary cilium have structural and functional similarities; both structures provide sensing and signalling platforms in cells.

  • Hedgehog signalling is associated with both primary cilia and immune synapses, which indicates, amongst other reasons, that the immune synapse could have arisen from the evolutionarily ancient primary cilium found in many organisms.

Abstract

Cytotoxic T lymphocytes (CTLs) kill virus-infected and tumour cells with remarkable specificity. Upon recognition, CTLs form a cytolytic immune synapse with their target cell, and marked reorganization of both the actin and the microtubule cytoskeletons brings the centrosome up to the plasma membrane to the point of T cell receptor signalling. Secretory granules move towards the centrosome and are delivered to this focal point of secretion. Such centrosomal docking at the plasma membrane also occurs during ciliogenesis; indeed, striking similarities exist between the cytolytic synapse and the primary cilium that throw light on the possible origins of immune synapses.

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Figure 1: Actin-rich interdigitations characterize the early but not the mature cytolytic synapse.
Figure 2: The order of events leading to polarized secretion at the CTL synapse.
Figure 3: Actin dynamics in migrating and synapsing CTLs.
Figure 4: Regulation of centrosome polarization to the immune synapse.
Figure 5: Structural similarities between the cytolytic synapse and the primary cilium.
Figure 6: Hedgehog signalling at the primary cilium and in CD8+ T cells.

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Acknowledgements

G.M.G. is funded by a Wellcome Trust Principal Research Fellowship (103930); M.D.R. is now funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (107609) and Cancer Research UK (C14303/A17197).

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  1. Maike de la Roche

    Present address: Present address: CRUK-Cambridge Research Institute, Cambridge CB2 0RE, UK.,

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  1. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK

    Maike de la Roche, Yukako Asano & Gillian M. Griffiths

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PowerPoint slides

Glossary

Immune synapse

The interface formed upon receptor-mediated recognition between an immune cell and an antigen-presenting cell.

Perforin

A pore-forming protein that is stored in the cytolytic granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells.

Granzymes

Cytolytic granule-contained serine proteases that cleave substrates in the cytoplasm of target cells, triggering rapid apoptosis.

Centrosomes

Usually consist of two centrioles surrounded by pericentriolar material and are the only microtubule-organizing centres (MTOCs) in T cells.

Microtubule-organizing centre

(MTOC). A structure found in eukaryotic cells, where the minus ends of microtubules are anchored and from which the plus ends of microtubules extend. Cells can contain multiple MTOCs.

Artificial planar synapses

Synapses formed between T cells and lipid bilayers containing stimulatory ligands (for example, peptide–MHC complexes) supported on a cover slip.

Partitioning defective polarity complex

(PAR polarity complex). A conserved protein complex that regulates cell polarity in eukaryotes and consists of PAR3, PAR6 and an atypical protein kinase C (such as PKCζ).

Pioneer microtubules

These microtubules extend from the microtubule-organizing centre (such as the centrosome) to the leading edge of cells.

Casein kinase 1δ

(CK1δ). A serine/threonine kinase that mediates the phosphorylation of tubulin, microtubule nucleation and the phosphorylation of microtubule-associated proteins.

Primary cilium

Immotile single hair-like extension from the plasma membrane formed by most cells that integrates signals from the environment.

Intraflagellar transport

(IFT). The bidirectional transport of protein complexes along microtubules in and out of the cilium or flagellum, which is required for ciliary assembly, resorption and signalling.

Transient receptor potential channel

(TRP channel). A large family of multifunctional ion channels, most of which are permeable to Ca2+.

Hedgehog signalling

(Hh signalling). An important signalling pathway for embryonic development and postnatal tissue maintenance in invertebrates and vertebrates. Mutations in this pathway can lead to cancer.

Smoothened

(SMO). A G protein-coupled receptor-like protein and the key signal transducer in the Hedgehog (Hh) signalling pathway.

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de la Roche, M., Asano, Y. & Griffiths, G. Origins of the cytolytic synapse. Nat Rev Immunol 16, 421–432 (2016). https://doi.org/10.1038/nri.2016.54

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