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  • Review Article
  • Published:

Regulation of T-cell activation by the cytoskeleton

Nature Reviews Immunology volume 7, pages 131–143 (2007)Cite this article

Key Points

  • Reorganization of the T-cell cytoskeleton is a rapid and dynamic process that is required to establish T-cell polarity and regulate cell–cell adhesion and T-cell activation.

  • Actin polymerization leading to lamellipodium and distal-pole formation facilitates T-cell–antigen-presenting-cell (APC) recognition.

  • Actin cytoskeletal reorganization in T cells is dependent on the dynamic interplay between actin regulatory, nucleating, capping and severing proteins.

  • Although Wiskott–Aldrich syndrome protein (WASP) and WASP-family verprolin-homologous protein-2 (WAVE2) regulate actin-related protein 2/3 (ARP2/3)-dependent actin polymerization in T cells, they clearly regulate distinct aspects of T-cell activation and filamentous (F)-actin-dependent events.

  • Microtubule-organizing centre (MTOC) polarization occurs in response to T-cell receptor (TCR) engagement and regulates directed release of cytolytic granules. This polarization requires both TCR-stimulated signalling pathways that affect actin reorganization and movement of microtubules by microtubule-associated proteins.

  • Signals arising from TCR microclusters not only induce F-actin polymerization but are themselves required for the stable formation and movement of TCR microclusters, and, ultimately, organization of the mature immunological synapse.

  • TCR-mediated integrin activation requires T-cell proximal signalling pathways that lead to cytoskeletal reorganization and the activation of RAP1. RAP1 can then act on downstream effectors including PKD, RAP1 ligand (RAPL), and RAP1-interacting adaptor protein (RIAM), leading to cytoskeletal reorganization and integrin clustering.

  • Signalling complexes that are formed at activated integrins in T cells contain proteins that are found in other cell types at focal adhesions.

  • The actin regulatory protein WAVE2 is required for integrin activation, and integrin scaffolding proteins including talin might act as linkers between newly generated F-actin and cell-surface integrins.

Abstract

To become activated, T cells must efficiently recognize antigen-presenting cells or target cells through several complex cytoskeleton-dependent processes, including integrin-mediated adhesion, immunological-synapse formation, cellular polarization, receptor sequestration and signalling. The actin and microtubule systems provide the dynamic cellular framework that is required to orchestrate these processes and ultimately contol T-cell activation. Here, we discuss recent advances that have furthered our understanding of the crucial importance of the T-cell cytoskeleton in controlling these aspects of T-cell immune recognition.

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Figure 1: Regulation of F-actin polymerization during the T-cell–antigen-presenting cell (APC) interaction.
Figure 2: TCR-mediated F-actin polarization.
Figure 3: T-cell receptor (TCR)-mediated microtubule-organizing centre (MTOC) polarization.
Figure 4: Pathways that contribute to T-cell receptor (TCR)-mediated integrin activation in T cells.

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Acknowledgements

The authors apologize to many colleagues whose exciting and important work was not quoted here owing to space constraints. We would like to thank J. Burkhardt, Y. Shimizu and P. Leibson for helpful discussions and critical review of the manuscript. This work was supported by the Mayo Foundation and grants from the US National Institutes of Health.

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Authors and Affiliations

  1. Department of Immunology, Mayo Clinic College of Medicine, 200 First Street South West, Rochester, 55905, Minnesota, USA

    Daniel D. Billadeau, Jeffrey C. Nolz & Timothy S. Gomez

  2. Department of Oncology Research, Mayo Clinic College of Medicine, 200 First Street South West, Rochester, 55905, Minnesota, USA

    Daniel D. Billadeau

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  1. Daniel D. Billadeau
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  2. Jeffrey C. Nolz
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  3. Timothy S. Gomez
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Correspondence to Daniel D. Billadeau.

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Glossary

Immunological synapse

A large junctional structure that is formed at the cell surface between a T cell that is interacting with an APC; it consists of molecules required for adhesion and signalling. This structure is important in establishing T-cell adhesion and polarity, is influenced by the cytoskeleton, and transduces highly controlled secretory signals, thereby allowing the directed release of cytokines or lytic granules towards the APC or target cell.

Actin-severing proteins

These proteins are activated downstream of cell-surface receptors and cleave filamentous actin, thereby promoting new actin-filament growth.

Actin-capping proteins

These proteins bind to the barbed end of filamentous actin and prevent further actin polymerization.

Actin-regulatory proteins

These proteins regulate actin dynamics through their associations with filamentous actin, either directly or by promoting actin nucleation through regulation of actin nucleators.

Actin-nucleating proteins

These proteins can facilitate actin nucleation through binding either the plus (barbed) or minus end of F-actin in conjunction with their binding to monomeric (G)-actin or G-actin–profilin complexes.

Microtubule-organizing centre

(MTOC). A structure that is found in all plant and animal cells, from which microtubules radiate. The two most important types of MTOCs are the basal bodies that are associated with cilia and the centrosome, which is composed of γ-tubulin-ring complexes for microtubule nucleation.

Distal-pole complex

A rigid membrane projection with cytoskeletal components that is formed during the process of T-cell–APC recognition. It is located at the back of the cell, opposing the lamellipodium and immunological synapse and is proposed to function in polarity and as a sink for negative regulators of T-cell activation.

Central and peripheral supramolecular activation clusters

(cSMAC and pSMAC). During T-cell activation, TCRs accumulate into a central cluster (known as the cSMAC) at the interface between the T cell and the APC. The cSMAC is surrounded by a leukocyte-function-associated antigen-1 (LFA1)-integrin ring (known as the pSMAC) in a bulls-eye fashion, and this characteristic receptor organization (cSMAC surrounded by the pSMAC) constitutes the mature immunological synapse.

Lipid raft

Structures that are proposed to arise from phase separation of different plasma membrane lipids as a result of the selective coalescence of certain lipids on the basis of their physical properties. This results in the formation of distinct and stable lipid domains in membranes that might provide a platform for membrane-associated protein organization.

T-cell receptor (TCR) microclusters

Accumulated TCR–peptide–MHC complexes that continuously form during T-cell activation and are thought to be localized sites of antigen recognition and T-cell activation.

Lamellipodium

A flattened, sheet-like protrusion that is supported by a meshwork of F-actin and extends at the leading edge of crawling cells.

ARP2/3 complex

The actin-related protein-2/3 (ARP2/3) complex is composed of seven proteins, including ARP2, ARP3, and the ARP complex protein-1 (ARPC1)–ARPC5. On its own, the complex has little activity but when bound to an ARP2/3-nucleation-promoting factor, it is activated to generate new actin filaments off pre-existing filaments.

ERM family proteins

Ezrin, radixin and moesin (ERM) proteins act as general cytolinkers between the cortical actin-filament network and the plasma membrane, and are thought to function mainly through their ability to bind both F-actin and the cytoplasmic regions of integral membrane proteins.

Wiskott–Aldrich syndrome

(WAS). A rare X-linked recessive disease that is caused by mutations in the WAS gene, and is characterized by immune dysregulation (immunodeficiency, eczema and autoimmunity) and thrombocytopaenia (decreased platelet number).

RNA interference

(RNAi). RNAi is a method of post-transcriptional control of gene expression, in which the introduction of small, sequence-specific, double-stranded RNAs into cells leads to the degradation of mRNAs that have a complementary sequence.

Minus end

The slow-growing end of a microtubule, which is anchored to the centrosome.

Total internal reflection fluorescence microscopy

(TIRFM). This microscopy method allows the identification of fluorescence within 100–200 nm of the interface between cells and their substrate (for example, lipid bilayers or glass coverslips), thereby providing a high lateral and axial resolution at the cell–substrate interface and the ability to observe nanoscale movement of signalling molecules during cellular activation.

Common variable immunodeficiency syndrome

(CVID). The most common symptomatic primary antibody deficiency, which is characterized by decreased levels of serum immunoglobulin and a low or normal number of B cells.

Calcium-regulated activated calcium (CRAC) channels

In several cell types, receptor-mediated signalling that leads to the depletion of endoplasmic-reticulum intracellular stores of calcium by PLCγ1-generated IP3 results in capacitive calcium entry from the outside of the cell through CRAC channels.

Inside-out signalling

The process by which intracellular signalling mechanisms result in the activation of a cell-surface receptor. By contrast, outside-in signalling is the process by which ligation of a cell-surface receptor activates signalling pathways inside the cell.

Extravasation

The cellular process in which circulating leukocytes bind to and migrate through the endothelium into the underlying tissue.

Phorbol 12-myristate 13-acetate

(PMA). PMA is a synthetic diacylglycerol analogue and potent pharmacological agent that is often used to stimulate activation of PKC-family members independently of receptor stimulation.

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Billadeau, D., Nolz, J. & Gomez, T. Regulation of T-cell activation by the cytoskeleton. Nat Rev Immunol 7, 131–143 (2007). https://doi.org/10.1038/nri2021

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