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  • Review Article
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Role of the cytoskeleton during leukocyte responses

Nature Reviews Immunology volume 4, pages 110–122 (2004)Cite this article

Key Points

  • The leukocyte cytoskeleton is required to carry out dynamic immune functions.

  • The same basic mechanisms underlie actin regulation during cell migration and effector functions, and extracellular signals govern the formation of different signalling complexes to provide specific signals.

  • Microfilaments provide the leukocyte with plasticity to undergo extravasation, which depends on extracellular signals. Endothelial cells also undergo actin remodelling during extravasation to allow leukocyte transit without irreversibly compromising the integrity of the vessel wall.

  • Leukocyte polarity provides an excellent platform for leukocytes to explore their surroundings, gathering positional information and providing optimized responses during migration and activation.

  • T-cell–antigen-presenting cell (APC) cognate interactions and cytotoxic T lymphocyte (CTL)-mediated killing require intimate contacts between effector and target cells, which is optimized by cortical actin rearrangements. In turn, polarized vesicle secretion depends on microtubule repositioning towards the cellular interface.

  • Phagocytosis uses actin polymerization to surround the target particle and actomyosin contraction to squeeze and engulf it, closing the phagosomal structure.

  • The actin cytoskeleton is actively used by leukocytes during effector functions, but other situations, such as apoptosis, include morphological changes that are associated with the dysregulation of key molecules.

  • Intracellular bacteria and viruses manipulate the cellular cytoskeleton to prevent clearance and optimize pathogen survival and growth inside cells.

Abstract

The cytoskeleton is a cellular network of structural, adaptor and signalling molecules that regulates most cellular functions that are related to the immune response, including migration, extravasation, antigen recognition, activation and phagocytosis by different subsets of leukocytes. Recently, a large number of regulatory elements and structural constituents of the leukocyte cytoskeleton have been identified. In this review, we discuss the composition and regulation of the different cytoskeletal elements and their role in immune responses.

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Figure 1: Leukocyte extravasation into target tissues.
Figure 2: Receptor and cytoskeleton asymmetry during leukocyte migration.
Figure 3: Rho GTPases and microfilament regulation.
Figure 4: The lymphocyte cytoskeleton during T-cell–APC interactions and the formation of the immunological synapse.
Figure 5: Type I phagocytosis.
Figure 6: Cytoskeletal subversion by pathogens in immune cells.

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Acknowledgements

The authors apologize to many colleagues whose important contributions have not been quoted due to space constraints, and thank R. Horwitz, X. Bustelo, B. Alarcón, A. G. Arroyo, R. Gónzalez-Amaro, J. L. Rodr'guez-Fernández, M. Gómez, M. Yáñez-Mó and M. Rey for critical reading of the manuscript, as well as members of the F. S. -M. laboratory for helpful discussions. This work has been supported by grants from the Ministerio de Ciencia y Tecnolog'a, Ayuda a la Investigación Básica Juan March 2002 and FIS CO3/01-Red Cardiovascular.

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Authors and Affiliations

  1. Servicio de Immunología, Hospital Universitario de la Princesa, c/Diego de León 62, Madrid, 28006, Spain

    Miguel Vicente-Manzanares & Francisco Sánchez-Madrid

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  1. Miguel Vicente-Manzanares
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  2. Francisco Sánchez-Madrid
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Correspondence to Francisco Sánchez-Madrid.

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DATABASES

LocusLink

beige

CAS

CD43

CD44

CD95

CD95L

CDC42

CHS1

DOCK180

EBP50

FAK

FOS

ICAM1

ILK

LFA1

NCK

PAK

PKC-β

PKN

PSGL1

RAB27

RAP1

VCAM1

VLA4

WASP

WIP

ZAP70

Glossary

CAPPING PROTEINS

Capping proteins bind to the growing (plus) end of microfilaments, blocking actin polymerization.

NUCLEATOR PROTEINS

Nucleator proteins bind to the plus or minus end of microfilaments and promote actin polymerization, binding to G-actin carriers and/or inducing conformational changes in microfilaments that promote its growth (nucleation).

ADAPTOR PROTEINS

Molecules that lack any known intrinsic enzymatic, DNA binding or receptor functions, but mediate protein–protein or lipid–protein interactions. Most function as flexible molecular scaffolds by regulating the spatio-temporal dynamics of specific effector molecules.

SELECTINS

Glycoproteins expressed by circulating blood cells or activated endothelial cells that support tethering and rolling through oligosaccharide-dependent interactions.

EZRIN–RADIXIN–MOESIN

(ERM). Adaptor proteins that connect plasma-membrane molecules to the actin cytoskeleton through the release of a head-to-tail autoinhibitory interaction, targeting proteins to specific regions of the plasma membrane such as microvilli and filopodia.

MICROVILLI

An actin-based protrusive structure that is mainly found in epithelial cells; it is also present in other cell types such as leukocytes, where they have a role in tethering and rolling.

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF

(ITAM). A structural motif containing tyrosine residues, found in the cytoplasmic tails of several signalling molecules. The tyrosine in the motif (Tyr-Xaa-Xaa-Leu/Ile) is a target for phosphorylation by SRC tyrosine kinases and subsequent binding of proteins that contain SH2 domains.

GTP EXCHANGE FACTOR

(GEF). These proteins catalyse the incorporation of GTP into the catalytic site of small GTPases, thereby acting as their activators.

AVIDITY

Avidity is the modulation of the ability of integrins to bind to their ligands, based not on the intrinsic affinity of each individual integrin molecule for its ligand, but by integrin clustering on the plasma membrane (increased number of integrin molecules per unit of membrane area), which results in increased binding capability.

AFFINITY

Integrin affinity is defined as the individual binding capability of integrins to their ligand(s), which is modulated by external factors that directly regulate integrin conformation, not their ability to cluster and therefore modulate their density on the plasma membrane.

G-PROTEIN-COUPLED RECEPTOR (GPCR) FAMILY

The largest family of membrane receptors, they bind small molecules (including chemoattractants), have seven transmembrane domains and signal through heterotrimeric G-proteins, resulting in cell activation.

LAMELLIPODIUM

Flat, fan-shaped, actin-rich structures involved in protrusion. They are usually generated in response to extracellular signals and direct cell-body migration.

UROPOD

A slender appendage formed at the trailing, rear edge of fast-migrating cells, such as amoeba, neutrophils or lymphocytes.

IMMUNOLOGICAL SYNAPSE

A structure that is formed at the cell–cell interface between a T cell and an antigen-presenting cell; also known as the supramolecular activation cluster (SMAC). Important molecules involved in T-cell activation — including the T-cell receptor, numerous signal transduction molecules and molecular adaptors — accumulate at this site. Mobilization of the actin cytoskeleton of the cell is required for formation of the immunological synapse.

PHAGOSOME

An actin-based structure that engulfs a phagocytosed particle induced by the activation of Fc receptors, which cluster many signal transduction molecules that are involved in actin polymerization and regulation.

TYPE III SECRETION SYSTEM

A set of secreted proteins that induce membrane and cytoskeleton changes used by bacteria to force their entry into cells.

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Vicente-Manzanares, M., Sánchez-Madrid, F. Role of the cytoskeleton during leukocyte responses. Nat Rev Immunol 4, 110–122 (2004). https://doi.org/10.1038/nri1268

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