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Homing and cellular traffic in lymph nodes

Key Points

  • Lymph nodes (LNs) are subdivided into three compartments: the lymphatic system, the blood circulation and the parenchyma, which is further subdivided into B-cell follicles and the T-cell area that together form the cortex, and the medulla. Cellular and molecular traffic between these compartments is an essential aspect of LN physiology.

  • Afferent lymph transports antigen and antigen-presenting dendritic cells (DCs) from peripheral tissues to draining LNs. The lymphatic system also functions as a one-way communication system along which molecular messages, such as chemokines, are transmitted to the cellular constituents of LNs.

  • Naive and central memory lymphocytes continuously enter LNs through high endothelial venules (HEVs) and return to the circulation by way of the efferent lymphatics.

  • Lymphocyte recruitment in HEVs involves a multi-step adhesion cascade that requires specific traffic molecules on both lymphocytes and HEVs. The respective T-cell and endothelial-cell-expressed homing molecules are: L-selectin and peripheral node addressin (for rolling); CC-chemokine ligand 21 (CCL21) and CC-chemokine receptor 7 (CCR7) (chemokine signal); and leukocyte function-associated antigen 1 (LFA1) and intercellular adhesion molecule 1 (ICAM1) or ICAM2 (for firm arrest).

  • DCs and their precursors enter LNs through afferent lymphatics and possibly also through HEVs. They process and present antigen from peripheral tissues and are essential for antigen-specific priming of naive T cells in LNs.

  • After entering the paracortex of LNs, T cells migrate rapidly and in random directions, contacting numerous DCs in search for a stimulating antigen. This behaviour seems to be cell autonomous and does not seem to be controlled by long-range chemotactic gradients.

  • Recent evidence indicates that the overall cellularity of LNs and, in particular, the egress of T cells from the cortex into efferent lymph vessels is tightly regulated and might involve sphingosine-1-phosphate and its receptors.

Abstract

Lymph nodes (LNs) are the organs where innate immune responses lead to acquired immunity, where some of our most devastating pathogens evade immunity, and where autoreactive lymphocytes first encounter tissue-specific self-antigens and are either tolerized or activated. The many roles of LNs depend on the coordinated migration of its cellular constituents. This article covers new insights into the organization and microvascular specialization of LNs, the guidance mechanisms that allow lymphocytes and antigen-presenting cells to find their correct place in the nodal parenchyma; and the role of afferent lymph flow in LN function.

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Figure 1: Lymph-node architecture.
Figure 2: Lymph-node microcirculation.
Figure 3: Lymph conduits and exclusion of large molecules from the lymph-node parenchyma.
Figure 4: Remote control of monocyte recruitment to lymph nodes in inflammation.
Figure 5: Interstitial traffic signals for T-cell and dendritic-cell migration in lymph nodes.

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Acknowledgements

We thank the members of the von Andrian lab for critical reading of this article. This work was supported by grants from the National Institutes of Health and the Dana Foundation.

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Correspondence to Ulrich H. von Andrian.

Supplementary information

41577_2003_BFnri1222_MOESM1_ESM.mov

Movie 1 | | Lymph-node microcirculation. This movie shows the location of B cells (green) and T cells (red) in the lymph node, relative to the microcirculation (which has been visualized by injection of a mixture of red and green fluorescent dextrans, and appears yellow). B cells are located in the distal B-cell follicles, whereas T cells remain in the paracortex. (MOV 4604 kb)

41577_2003_BFnri1222_MOESM2_ESM.mov

Movie 2 || Lymph conduits. Injection of fluorescent dextran (green) into the skin allows visualization of the afferent lymph vessel in a mouse popliteal lymph node. The lymph fluid accumulates below the lymph-node capsule (blue). (MOV 3901 kb)

41577_2003_BFnri1222_MOESM3_ESM.mov

Movie 3 || Exclusion of large molecules from the lymph-node parenchyma. This movie shows that the fluorescent lymph remains confined to the subcapsular sinus and does not penetrate the lymph-node parenchyma. (MOV 2414 kb)

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DATABASES

LocusLink

CCL2

CCL19

CCL21

CCR7

CD31

CD43

CD44

CD62L

CXCL9

CXCL12

CXCL13

CXCR3

CXCR4

CXCR5

DARC

ICAM1

LFA1

MADCAM1

VAP1

FURTHER INFORMATION

Ulrich von Andrian's laboratory

Glossary

FOLLICULAR DENDRITIC CELLS

(FDCs). Stromal cells of non-haemopoietic origin in B-cell follicles that present intact antigen to B cells and function in the selection of memory B cells during germinal-centre reactions.

HIGH ENDOTHELIAL VENULES

(HEVs). A specialized type of postcapillary venule that is lined by cuboid or high endothelial cells. HEVs are only found in secondary lymphoid organs, except the spleen. They are the main site of lymphocyte entry from the blood.

INTEGRIN ACTIVATION

The process by which integrins are triggered, often by chemokines or other signals (for example, T-cell receptor stimulation), to switch from a low- to a high-affinity ligand-binding state. This entails a conformational change in the extracellular domain of the integrin heterodimer. In addition, integrins might be redistributed into clusters on the cell surface to enhance binding avidity.

DIAPEDESIS

The passage of cells across a cellular barrier, such as the monolayer of tightly apposed endothelial cells in postcapillary venules.

DENDRITIC-CELL MATURATION

The process by which dendritic cells (DCs) are reprogrammed from a mainly antigen collecting to an antigen presenting, immunostimulatory mode. Maturation can be induced by signals associated with tissue damage, inflammation or infection, resulting in enhanced cell-surface presentation of MHC complexes and co-stimulatory molecules and altered trafficking, enabling them to enter the T-cell area of secondary lymphoid tissues.

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von Andrian, U., Mempel, T. Homing and cellular traffic in lymph nodes. Nat Rev Immunol 3, 867–878 (2003). https://doi.org/10.1038/nri1222

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