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Lymphocyte trafficking across high endothelial venules: dogmas and enigmas

Nature Reviews Immunology volume 4, pages 360–370 (2004)Cite this article

Key Points

  • To mediate an effective immune response, lymphocytes must find their way to secondary lymphoid tissues, such as the lymph nodes, the Peyer's patches and the spleen, where antigens and antigen-presenting dendritic cells are selectively localized.

  • When entering lymph nodes and Peyer's patches, lymphocytes selectively adhere to and transmigrate through the high endothelial venules (HEVs), which are distinct from normal venules in several ways.

  • HEVs express unique adhesion molecules (vascular addressins) that function as ligands for lymphocyte homing receptors. They also express several lymphoid chemokines that can activate integrins on circulating lymphocytes.

  • Accumulating evidence indicates that chemokines produced in and around HEVs have a crucial role in lymphocyte trafficking to lymph nodes and Peyer's patches. Nevertheless, the way that chemokines function in vivo is not fully understood.

  • Numerous chemokine-binding molecules are expressed in and immediately around HEVs. Certain chemokines bind preferentially to certain chemokine-binding molecules that seem to be expressed in a concentric manner in the HEV area.

  • We propose that each chemokine-binding molecule provides a substrate to present the appropriate bound chemokine and that lymphocytes expressing appropriate chemokine receptors respond to these matrix-presented chemokines successively. This would result in directed trafficking of lymphocytes across HEVs and into the lymph-node parenchyma.

  • Lymphocytes might respond to these chemokines by haptotaxis and/or chemokinesis, rather than by chemotaxis.

  • Numerous questions remain unanswered concerning the physiology and function of HEVs.

Abstract

Lymphocytes are intrinsically mobile and circulate continuously between the blood and secondary lymphoid tissues. When naive lymphocytes first enter lymph nodes and Peyer's patches, they adhere to and migrate across specific blood vessels known as high endothelial venules (HEVs). The local availability of chemokines in or near HEVs is crucial for the specificity of this process. Here, we summarize recent studies of the chemokine-directed events in lymphocyte trafficking across HEVs, and we examine the dogmas and enigmas concerning lymphocyte migration to lymph nodes and Peyer's patches. A model is also discussed, in which we propose that the response to chemokines immobilized on extracellular-matrix components is important for lymphocyte positioning in vivo.

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Figure 1: Cell trafficking into and out of lymph nodes.
Figure 2: Chemokines and chemokine-binding molecules expressed in and around high endothelial venules (HEVs) in a concentric manner might function coordinately in lymphocyte trafficking across HEVs.
Figure 3: Chemotaxis, haptotaxis or chemokinesis?

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Acknowledgements

We thank R. Pabst, J. Westermann and T. Hirata for critically reading the manuscript. We also thank members of the Laboratory of Molecular and Cellular Recognition for discussions and suggestions. We thank the Japanese Ministry of Education, Culture, Sports, Science and Technology for continuous grant support.

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Authors and Affiliations

  1. Laboratory of Molecular and Cellular Recognition, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, 565-0871, Suita, Japan

    Masayuki Miyasaka & Toshiyuki Tanaka

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  1. Masayuki Miyasaka
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  2. Toshiyuki Tanaka
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Correspondence to Masayuki Miyasaka.

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DATABASES

LocusLink

CCL2

CCL5

CCL19

CCL21

CCR7

CD105

CXCL1

CXCL9

CXCL10

CXCL12

CXCL13

CXCR3

CXCR4

DARC

ICAM1

ICAM2

LFA1

MAC25

MADCAM1

VCAM1

VLA4

FURTHER INFORMATION

Masayuki Miyasaka's lab

Glossary

PEYER'S PATCHES

Groups of lymphoid nodules that are present in the small intestine (usually the ileum). They occur massed together on the intestinal wall, opposite the line of attachment of the mesentery. Peyer's patches consist of a dome area, B-cell follicles and interfollicular T-cell areas. High endothelial venules are present mainly in the interfollicular areas.

HIGH ENDOTHELIAL VENULES

(HEVs). Venules (small veins that join capillaries to larger veins) that have a high-walled endothelium and are present in the paracortex of lymph nodes and tonsils, as well as in the interfollicular areas of Peyer's patches.

BASAL LAMINA

A supporting structure located at the boundary between endothelia (or epithelia) and the underlying connective tissue. In blood vessels, the basal lamina surrounds the endothelial cells and pericytes, providing physical support. It is composed mainly of collagen IV and laminin molecules. Fibronectin is also present on the connective-tissue face. The basal lamina also seems to be involved in maintaining and modulating endothelial-cell functions by capturing various humoral factors.

INTERFOLLICULAR HEVS

High endothelial venules (HEVs) located in the interfollicular area — the T-cell-dependent area of the lymph-node cortex, which lies between B-cell follicles. Most HEVs belong to this category.

FOLLICULAR HEVS

High endothelial venules (HEVs) located within B-cell follicles.

PARAFOLLICULAR HEVS

High endothelial venules (HEVs) found near, but not within, B-cell follicles.

DRY MOTIF

An amino-acid motif composed of aspartic acid (D), arginine (R) and tyrosine (Y). It is highly conserved among G-protein-coupled receptors and is thought to be essential for G-protein-mediated signalling.

INTRAVITAL MULTI-PHOTON LASER MICROSCOPY

Multi-photon laser microscopy combines the advanced optical techniques of laser-scanning confocal microscopy with long-wavelength multi-photon fluorescence excitation to capture high-resolution, three-dimensional images of living cells and/or tissues that have been labelled with fluorophores. It provides a greater tissue imaging depth (up to 350 μm depending on the tissue) and less photobleaching and phototoxicity than conventional imaging methods.

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Miyasaka, M., Tanaka, T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat Rev Immunol 4, 360–370 (2004). https://doi.org/10.1038/nri1354

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