Dendritic-cell trafficking to lymph nodes through lymphatic vessels

Key Points

  • The migration of dendritic cells (DCs) to lymph nodes from the periphery supports the onset of immune responses. Whereas several molecules that are required for DCs to leave the periphery have now been defined, much remains to be discovered about how DCs enter and pass through the lymphatic vessels to reach the T-cell zone of the lymph node.

  • Initial afferent lymphatic vessels are organized as small capillaries that support DC entry. These vessels converge with larger collecting vessels that, ultimately, arrive and branch at the subcapsular sinus of the lymph node.

  • The collecting vessels operate as intrinsic pumps that might participate in driving DCs to the lymph node.

  • DCs approach lymphatic vessels by chemotaxis that depends mainly on the chemokine receptor CC-chemokine receptor 7 (CCR7).

  • Data from mice that have mutations in the ligands for CCR7 do not indicate the location where CCR7 and its ligands act during migration to the lymph node, although it is possible that lymphatic-vessel-derived CCR7 ligands are required to promote DC trafficking into the lymph and the lymph nodes.

  • The biophysical environment — including the flow of interstitial fluid, which naturally runs towards lymphatic vessels — probably positively influences the movement of DCs towards lymphatic vessels by operating together with DC-mediated proteolysis. Interstitial flow might also affect the signalling induced by chemokines.

  • The migration of different populations of DCs to lymph nodes utilizes shared and unique molecules that support trafficking. Most data are derived from studying the migration of skin DCs, and it remains to be determined whether these findings are applicable to DCs in other tissues.

  • Several assays to study DC migration have been developed, and each has particular advantages and disadvantages. Assays that directly analyse DCs while they are in transit through lymphatic vessels are expected to yield the most ground-breaking findings in the future.

  • Manipulating DC migration to influence immune responses in clinical settings holds promise, but several areas require further investigation for this hope to become a reality.

Abstract

Antigen-presenting dendritic cells often acquire foreign antigens in peripheral tissues such as the skin. Optimal encounter with naive T cells for the presentation of these antigens requires that the dendritic cells migrate to draining lymph nodes through lymphatic vessels. In this article, we review important aspects of what is known about dendritic-cell trafficking into and through lymphatic vessels to lymph nodes. We present these findings in the context of information about lymphatic-vessel biology. Gaining a better understanding of the crosstalk between dendritic cells and lymphatic vessels during the migration of dendritic cells to lymph nodes is essential for future advances in manipulating dendritic-cell migration as a means to fine-tune immune responses in clinical settings.

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Figure 1: Lymphatic-vessel organization in the skin.
Figure 2: Terminal afferent lymphatic vessels in lymph nodes.
Figure 3: Tracing dendritic-cell migration to lymph nodes.
Figure 4: Expression of CC-chemokine-receptor-7 ligands and fate of dendritic cells in wild-type and plt mice.
Figure 5: Potential mechanism of flow-enhanced autologous chemotaxis or secreted matrix-metalloproteinase redistribution.

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Acknowledgements

We thank M. Fleury for producing figure 5.

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Correspondence to Gwendalyn J. Randolph.

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DATABASES

Entrez Gene

CCL19

CCL21

CCR7

ICAM1

JAM1

LFA1

MMP2

MMP9

Glossary

TWO-PHOTON MICROSCOPY

A fluorescence-imaging technique that takes advantage of the fact that fluorescent molecules can absorb two photons simultaneously during excitation, before they emit light. This technique greatly reduces photodamage of living specimens, improves depth of tissue penetration, allows distinct separation between excitation and emission wavelengths, and confines excitation to a discrete focal point.

CONTACT ELICITATION

The inflammatory immune reactions that occur at the site of exposure after contact with a sensitizing antigen. These reactions occur after second and subsequent exposures to a particular sensitizing antigen, and they involve the recruitment and responses of effector T cells.

FLUORESCEIN-ISOTHIOCYANATE PAINTING ASSAY

(FITC painting). An experimental assay of contact sensitization in mice. In this assay, the contact-sensitizing substances are dibutyl phthalate and the fluorochrome FITC, which also functions as a migration tracer. The application of this mixture to the skin, in an equal volume of acetone, is often called painting.

CONTACT SENSITIZATION

The initial reaction that occurs after the first exposure to a 'sensitizer' hapten or antigen. This step requires dendritic-cell migration to lymph nodes to prime contact-antigen-specific T cells.

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Randolph, G., Angeli, V. & Swartz, M. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol 5, 617–628 (2005). https://doi.org/10.1038/nri1670

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