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  • Review Article
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Rho family GTPases and their regulators in lymphocytes

Nature Reviews Immunology volume 9, pages 630–644 (2009)Cite this article

Key Points

  • In mammals, the Rho family of GTPases has 23 members, which are regulated by 79 guanine nucleotide exchange factors (GEFs), 65 GTPase-activating proteins (GAPs) and 3 guanine nucleotide dissociation inhibitors (GDIs). About half of these are expressed by lymphocytes.

  • RAC1 and RAC2 have overlapping and redundant roles in B and T cell development, activation and migration.

  • RHOH has an important role in T cell activation as an adaptor protein, recruiting ζ-chain-associated protein kinase of 70 kDa (ZAP70) to the plasma membrane.

  • The VAV1, VAV2 and VAV3 GEFs have overlapping and redundant roles in B and T cell development and activation but not migration. VAV1 has GEF-independent functions, possibly as an adaptor protein.

  • The GEF DOCK2 (dedicator of cytokinesis2) is a crucial transducer of chemokine receptor signals in both B and T cells, and is also required for T cell activation.

  • The GEF SWAP70 (switch-associated protein 70)is required for polarization of B cells and transmigration across high endothelial venules. The related GEF IBP regulates T helper cell differentiation, in part by binding the transcription factor interferon-regulatory factor 4, a function that might be GEF independent.

Abstract

Rho family GTPases, and the proteins that regulate them, have important roles in many cellular processes, including cell division, survival, migration and adhesion. Although most of our understanding of these proteins has come from studies using cell lines, more recent gene targeting studies in mice are providing insights into the in vivo function of these proteins. Here we review recent progress revealing crucial roles for these proteins in lymphocyte development, activation, differentiation and migration. The emerging picture shows that Rho family GTPases transduce signals from receptors for antigens, chemokines and cytokines, as well as adhesion molecules and pattern recognition receptors, and that they function as focal points for crosstalk between different signalling pathways.

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Figure 1: Mouse Rho GTPases.
Figure 2: Regulation of Rho GTPases.
Figure 3: Role of Rho GTPases and their regulators in B cell development and function.
Figure 4: Signal transduction from the B cell receptor.
Figure 5: Signal transduction from G protein-coupled receptors and integrins.
Figure 6: Role of Rho GTPases and their regulators in T cell development and function.
Figure 7: Signal transduction from the T cell receptor.

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Acknowledgements

We thank S. Saveliev and E. Schweighoffer for critical reading of the manuscript, A. Ridley for discussions, and S. Shah (Bloomsbury Centre for Bioinformatics, UCL) for analysis of the transcriptome data.

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  1. Division of Immune Cell Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA, London, UK

    Victor L. J. Tybulewicz & Robert B. Henderson

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Correspondence to Victor L. J. Tybulewicz.

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Expression of Rho GTPases and their regulators in lymphocytes (PDF 107 kb)

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Glossary

Prenyl group

An isoprenoid lipid, either farnesyl or geranylgeranyl. Most Rho GTPases are modified by the addition of a prenyl group at their carboxyl terminus. This modification anchors Rho GTPases in membranes.

Follicular B cell

A circulating mature B cell subset that populates the follicles of secondary lymphoid organs such as the spleen, lymph nodes and Peyer's patches.

Marginal zone B cell

A non-circulating B cell subset found mainly in the marginal zone of the spleen, which is located between the non-lymphoid red pulp and the lymphocyte-rich white pulp. These cells are thought to mount early responses to blood-borne antigens.

B-1 cell

A cell belonging to the B cell lineage that populates the peritoneal and pleural cavities and secretes polyspecific, low-affinity IgM.

Transitional B cell

An immature B cell subset found in the spleen having recently arrived from the bone marrow. These cells are short-lived, with half-lives of 24 days, and mature into follicular or marginal zone B cells.

Immunological synapse

A region that can form between two cells of the immune system in close contact. The immunological synapse originally referred to the interaction between a T cell and an antigen-presenting cell. It involves adhesion molecules, as well as antigen receptors and cytokine receptors. The immunological synapse is characterized by polarization of the lymphocyte, resulting, for example, in directed secretion towards the antigen-presenting cell.

G protein-coupled receptor

(GPCR). One of a large group of receptors that bind a diverse set of molecules, including chemokines, complement components, biologically active amines and neurotransmitters. GPCRs are seven-transmembrane-spanning receptors and are coupled to heterotrimeric, GTP-regulated signalling proteins.

Sphingosine 1 -phosphate

(S1P). A sphingolipid involved in signalling. In the immune system, S1P induces the egress of lymphocytes from lymphoid organs by binding to SIP receptors on the cells.

Intravital microscopy

This is used to examine biological processes, such as leukocyte–endothelial-cell interactions, in living tissue. In general, translucent tissues are used, such as the mesentery or cremaster muscle, or lymph nodes, which can be exposed and mounted for microscopic observation.

High endothelial venule

A specialized venule with a cuboidal endothelial lining. They are found in peripheral lymph nodes and Peyers patches. High endothelial venules are the sites of entry of lymphocytes into lymphoid tissues from the blood.

Lamellipodium

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

Uropod

A slender protrusion that forms at the trailing end of migrating leukocytes.

Positive selection

A process in the thymus that leads to the survival of immature thymocytes that express T cell receptors that bind with an appropriate affinity to self peptide–MHC complexes.

Negative selection

A process in the thymus that eliminates thymocytes that express T cell receptors that bind with high affinity to self peptide-MHC complexes.

γδ T cells

T cells that express the γδ T cell receptor. These T cells are present in the skin, vagina and intestinal epithelium as intraepithelial lymphocytes (IELs). Although the exact function of γδ T cells is unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses.

Ezrin, radixin and moesin (ERM) proteins

ERM proteins function 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.

Experimental autoimmune encephalomyelitis

(EAE). An experimental model of the human disease multiple sclerosis. EAE is an autoimmune disease mediated by CD4+ T helper 1 (TH1) cells and interleukin–17-producing TH17 cells reactive to components of the myelin sheath that infiltrate the nervous parenchyma, release pro-inflammatory cytokines and chemokines, promote leukocyte infiltration and contribute to demyelination.

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Tybulewicz, V., Henderson, R. Rho family GTPases and their regulators in lymphocytes. Nat Rev Immunol 9, 630–644 (2009). https://doi.org/10.1038/nri2606

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