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Physiology

Relax and come in

During inflammation, lymph nodes swell with an influx of immune cells. New findings identify a signalling pathway that induces relaxation in the contractile cells that give structure to these organs. See Letter p.498

Mechanical forces are key elements in the developmental control of organ size1. Adjusting the size of lymph nodes is a special challenge, because immune cells continually enter and exit the organs from the bloodstream, and the number of cells the nodes contain can rapidly increase during an immune or inflammatory response. Despite these dramatic changes in cellularity, the structural backbone of lymph nodes — a network of stromal fibroblastic reticular cells — remains relatively stable2. In this issue, Acton et al.3 (page 498) show that, during inflammation, immune cells called dendritic cells transmit a signal that triggers the physical relaxation of these stromal cells, thereby making space for more immune cells to enter the lymph nodes. This mechanical control aids rapid swelling of the organ, without substantial remodelling or proliferation of the stromal cells.

Lymph nodes are the sites of key immune-cell interactions. In these organs, dendritic cells (DCs) present pathogen molecules (antigens) carried in from peripheral tissues to lymphocytes (particularly T cells), which travel between lymph nodes through the blood and lymphatic circulation. In the lymph nodes, T cells rapidly fan out to scan the DCs for antigens that match their specific T-cell receptors. Although it is known that the same guidance cues attract DCs and T cells to a shared lymph-node compartment, it is unclear how the entry and exit of T cells is coordinated quantitatively. It has been suggested4 that, on exiting the bloodstream, T cells remain in a waiting position until there is enough space to enter the lymph node. Such mechanical regulation might balance influx and efflux, but this must shift during inflammatory states to allow for swelling of the organ and intensified scanning of DCs by T cells.

The network of fibroblastic reticular cells (FRCs) permeates the lymph node like the skeleton of a sponge. FRCs are the main producers of chemokines, the factors that attract DCs and T cells and keep them motile. The migrating cells also use the adhesive FRC surface as a guidance structure. In addition to these roles in orchestrating immune-cell traffic, the FRC network forms an interconnected system of micro-scale conduits, which are connected to the lymphatic system and bloodstream and serve as a system for distributing small molecules to resident DCs. Although FRCs have many characteristics of epithelial cells (which line the body's surfaces and cavities), they also express smooth-muscle actin5, a protein normally found in cell types that can physically contract.

Acton et al. show that FRCs do have contractile function and that they use this to tune the tension of the lymph node, demonstrating that it is not the capsule tissue surrounding the organ that restricts its size, but its internal scaffold. The authors investigated signalling in these cells through podoplanin, an FRC transmembrane protein that binds the receptor CLEC-2, which is induced on DCs following contact with pathogens. They found that, in the absence of CLEC-2 as a ligand, podoplanin transmits signals through proteins of the ERM family to the proteins GEF-H1 and RhoA, which regulate actin contractility mediated by the protein myosin II. This signalling maintains FRCs in a highly contractile state. Binding of podoplanin by CLEC-2 caused podoplanin to redistribute to another membrane compartment, where it stopped signalling to ERM proteins and thereby relaxed actomyosincontraction. This switched the cells from a contractile state dominated by actomyosin filaments to a protrusive, relaxed and elongated form.

These in vitro findings suggested a plausible scenario for events in vivo (Fig. 1). Activated DCs in the lymph nodes — either DCs that are activated in the periphery and migrate into the lymph node, or DCs resident in the lymph node that are activated by factors carried by the FRC conduit system — are induced to upregulate CLEC-2, causing relaxation of the FRCs. This loosens up the lymph-node structure, allowing influx of additional T cells and effectively expanding the volume of the organ.

Figure 1: Lymph-node swelling during the inflammatory response.
figure1

Immune cells, including lymphocytes and dendritic cells (DCs), continually enter and exit lymph nodes. The number of cells that the node can accommodate is restricted by the available space, which Acton et al.3 show is regulated by the contractile state of the fibroblastic reticular cells (FRCs) that form a network providing lymph-node structure. a, In the steady state, the FRCs are kept in a contracted state by activity of the transmembrane protein podoplanin, which signals through ERM proteins to RhoA and GEF-H1 (not shown), inducing myosin-II-mediated contraction of the actomyosin protein network. b, During inflammation, activation of DCs induces expression of the surface molecule CLEC-2, which binds podoplanin and switches off this signalling pathway. This leads to relaxation of the FRC network, allowing the lymph node to accommodate more lymphocytes and to swell.

In line with this model and previous studies2, Acton and colleagues found that, at early time points after an inflammatory stimulus in mice, when the cellularity and volume of their lymph nodes has already tripled, FRCs did not undergo significant proliferation. Instead, the spacing of the FRC network increased, indicating a stretched configuration of the cells. To test the potential involvement of podoplanin signalling in this process, the authors studied mice that were lacking CLEC-2 in DCs, and found that they show severely impaired lymph-node swelling after immunization. However, swelling was restored when podoplanin on FRCs was artificially bound by injecting the mice with CLEC-2 protein.

This newly identified mechanism for lymph-node relaxation is thought-provoking. Besides lymph nodes, podoplanin-expressing FRC-like cellular networks are found in the thymus, spleen and tumour-associated stroma, and may play a similar part in regulating the size and cellularity of these organs and tissues. If the size of the local immune compartment could be pharmacologically altered by tuning the contractile state, such networks might even serve as potential targets for immunomodulation. Podoplanin is also induced on most tissue fibroblast cells during inflammatory states6. In this situation, CLEC-2–podoplanin signalling might biomechanically resolve swelling and inflammation by squeezing the tissue once CLEC-2 levels drop with the disappearance of pathogenic stimuli.

Although it is highly plausible that DCs act as key messengers to mediate lymph-node relaxation, it seems probable that FRC contractility can also be tuned by other input signals. In this context, it is interesting to note that in many mammals (horses, dogs, humans and especially deep-diving seals), the spleen can contract under low-oxygen conditions to expel an 'emergency reservoir' of oxygenated red blood cells7. Furthermore, elevated numbers of white blood cells have been associated with spleen and lymph-node contractions, indicating that these responses, which are mainly triggered by nervous-system signals8, could also serve immunological functions.

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Correspondence to Michael Sixt.

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Vaahtomeri, K., Sixt, M. Relax and come in. Nature 514, 441–442 (2014). https://doi.org/10.1038/514441a

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