Review Article | Published:

HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes

Nature Reviews Immunology volume 12, pages 762773 (2012) | Download Citation

Abstract

In search of foreign antigens, lymphocytes recirculate from the blood, through lymph nodes, into lymphatics and back to the blood. Dendritic cells also migrate to lymph nodes for optimal interaction with lymphocytes. This continuous trafficking of immune cells into and out of lymph nodes is essential for immune surveillance of foreign invaders. In this article, we review our current understanding of the functions of high endothelial venules (HEVs), stroma and lymphatics in the entry, positioning and exit of immune cells in lymph nodes during homeostasis, and we highlight the unexpected role of dendritic cells in the control of lymphocyte homing through HEVs.

Key points

  • Lymph nodes are essential for the encounter of blood-derived naive lymphocytes with antigens and antigen-presenting cells, such as dendritic cells (DCs), which drain from peripheral tissues through interstitial fluids (lymph). The recirculation of lymphocytes through lymph nodes thus allows the extremely rare populations of naive lymphocytes specific for a given antigen to survey the lymph for the presence of their target antigen in any part of the body, thereby providing an effective immune surveillance for foreign invaders (such as viruses, bacteria and helminths) and for alterations in the body's own cells.

  • Naive lymphocytes circulating in the blood enter lymph nodes through high endothelial venules (HEVs), which are specialized blood vessels lined by plump endothelial cells. HEVs express high levels of sulphated sialomucins decorated with 6-sulpho sialyl Lewis X, which are ligands for the lymphocyte homing receptor L-selectin. Lymphocytes migrate through HEVs via a multistep adhesion cascade. First, rolling is initiated by L-selectin interactions with HEV sialomucins. Second, sticking (firm arrest) occurs after the activation of lymphocyte integrins by heparan sulphate-bound chemokines. Third, the lymphocytes crawl on the HEV luminal surface. Fourth, the cells rapidly transmigrate across the HEV endothelium via exit ramps.

  • CD11c+ DCs, which are strategically positioned close to HEV walls in vivo, have a crucial role in the regulation of HEV-mediated lymphocyte homing to lymph nodes. It has been shown recently that, in the absence of DCs, the mature adult HEV phenotype reverts to an immature neonatal phenotype, and lymphocyte sticking to HEVs is inhibited.

  • Rather than entering lymph nodes through HEVs (the 'blood' route), some immune cells use the 'lymph' route, particularly DCs that enter terminal lymphatics in the skin, circulate in lymph and then migrate to skin-draining lymph nodes through afferent lymphatics. Lymph nodes are often organized in chains, and naive T cells leaving a peripheral primary lymph node via efferent lymphatics, after entering through HEVs, may also enter downstream secondary lymph nodes through afferent lymphatics.

  • After entering the lymph node through HEVs or lymphatics, lymphocytes and DCs traffic to their respective subcompartments: the paracortical T cell areas for T cells and DCs; and the follicles for B cells. Stromal cell networks formed by fibroblastic reticular cells and follicular dendritic cells, together with stromal cell-derived lymphoid chemokines (namely CCL21, CCL19 and CXCL13), have key roles in guiding immune cells to these lymph node subcompartments.

  • After exploring a given lymph node for several hours, naive lymphocytes that do not encounter their target antigen leave the lymph node through efferent lymphatics. Recent two-photon intravital microscopy analyses indicate that B and T cells exit lymph nodes through cortical sinuses, after sensing sphingosine-1-phosphate (S1P) egress signals from lymphatics via S1P receptor type 1.

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Acknowledgements

We thank M. Sixt and A. Peixoto for helpful comments on the manuscript. Work in the laboratory of J.-P.G. is supported by grants from Fondation ARC pour la Recherche sur le Cancer, Agence Nationale de la Recherche (ANR), Institut National du Cancer (INCA), Fondation RITC and Région Midi-Pyrénées. Research by R.F. is supported by Deutsche Forschungsgemeinschaft (DFG) grants SFB621-A1, SFB738-B5, SFB587-B3, SFB900-B1 and KFO 250-FO 334/2-1. We regret that, owing to space limitations, we could not always quote the work of colleagues who have contributed to the field.

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    • Christine Moussion

    Present address: Institute of Science and Technology (IST) Austria, A-3400 Klosterneuburg, Austria.

Affiliations

  1. CNRS, Institut de Pharmacologie et de Biologie Structurale (IPBS), 205 Route de Narbonne, F-31077 Toulouse, France.

    • Jean-Philippe Girard
    •  & Christine Moussion
  2. Universit de Toulouse, UPS, IPBS, F-31077 Toulouse, France.

    • Jean-Philippe Girard
    •  & Christine Moussion
  3. Institute of Immunology, Hannover Medical School, D-30625 Hannover, Germany.

    • Reinhold Förster

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jean-Philippe Girard.

Glossary

Lymph

Interstitial protein-poor aqueous fluid in the extravascular space that is channelled in lymphatic vessels and returned to the circulation via the thoracic duct.

High endothelial venules

(HEVs). Specialized venules (small veins that join capillaries to larger veins) that are lined by plump endothelial cells. HEVs occur in secondary lymphoid organs, except the spleen, and are the main sites of lymphocyte entry from the blood.

Fibroblastic reticular cells

(FRCs). Specialized reticular fibroblasts located in the T cell areas of lymph nodes and other secondary lymphoid organs that produce collagen-rich reticular fibres and form stromal networks and conduits that are important for the trafficking of immune cells.

Follicular dendritic cells

(FDCs). Specialized reticular fibroblasts located in B cell follicles of lymph nodes and other secondary lymphoid organs that present intact antigens to B cells.

Cortical sinuses

Blind-ended lymphatic vessels located in the T cell areas of lymph nodes that mediate the exit of B and T cells from the lymph nodes.

Two-photon intravital microscopy

A fluorescence imaging technique that combines laser-scanning confocal microscopy with long-wavelength multiphoton fluorescence excitation to capture high-resolution three-dimensional images of fluorescent cells or tissues in living animals.

Haptotactic gradients

Gradients of surface-bound ligands that promote directional, receptor-dependent migration of cells towards areas of higher concentrations.

Pertussis toxin

A toxin that blocks Gαi-coupled receptor signalling (including chemokine receptor signalling) by catalysing ADP ribosylation of the Gαi subunit.

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https://doi.org/10.1038/nri3298

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