Journal Article

Dendritic cells control fibroblastic reticular network tension and lymph node expansion

Mourão-Sá, Diego, Sahai, Erik, Rosewell, Ian, Acton, Sophie E., Snelgrove, Kathryn J., Hooper, Steven, Turley, Shannon J., Astarita, Jillian L., Moita, Luis F., Jenkins, Robert P., Rogers, Neil C., Nye, Emma, Stamp, Gordon, Farrugia, Aaron J., van Blijswijk, Janneke, Reis e Sousa, Caetano

2014

Overview

During inflammation, the lymph node stromal compartment is shown to accommodate high numbers of infiltrating lymphocytes by relaxing the cytoskeleton of fibroblastic reticular cells, allowing the latter to stretch and the lymph node to expand. The mechanism of lymph node expansion Lymph nodes are dynamic structures that must respond rapidly to large cellular influxes provoked by local inflammation. However, how the lymph node stromal compartment reacts to accommodate lymph node expansion remains unclear. This study shows that the lymph node stromal compartment can accommodate large numbers of infiltrating lymphocytes by relaxing the cytoskeleton of fibroblastic reticular cells, allowing the cells to stretch and the lymph node to expand. This lymph node remodelling reaction is driven by the interaction of CLEC-2 protein on incoming antigen-presenting dendritic cells with podoplanin on fibroblastic reticular cells. After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph node cellularity, leading to organ expansion 1 , 2 . Here we report that the physical elasticity of lymph nodes is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells. We show in mouse cells that PDPN induces actomyosin contractility in FRCs via activation of RhoA/C and downstream Rho-associated protein kinase (ROCK). Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of CLEC-2 protein to immunized mice augments lymph node expansion. In contrast, lymph node expansion is significantly constrained in mice selectively lacking CLEC-2 expression in dendritic cells. Thus, the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes 3 also initiate remodelling of lymph nodes by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid lymph node expansion—driven by lymphocyte influx and proliferation—that is the critical hallmark of adaptive immunity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14/63 / 38/109 / 38/35 / 38/89 / 42/70 / 631/250/1620/1616 / 631/250/256/2516 / 631/80/128/1276 / 631/80/2373 / 64/60 / 82/51 / 96/106 / 96/31 / 96/33 / 96/63 / Actomyosin - metabolism / Animals / Cell interaction / Cell Membrane - metabolism / Cell research / Cells / Cellular signal transduction / Cytoskeleton / Cytoskeleton - metabolism / Dendritic cells / Dendritic Cells - immunology / Dendritic Cells - physiology / Female / Fibroblasts - cytology / Fibroblasts - physiology / Humanities and Social Sciences / Immunization / Inflammation - immunology / Lectins, C-Type - metabolism / letter / Ligands / Lipids / Lymph nodes / Lymph Nodes - cytology / Lymph Nodes - immunology / Lymph Nodes - metabolism / Lymphatic system / Lymphocytes / Male / Membrane Glycoproteins - metabolism / Mice / multidisciplinary / Phosphorylation / Physiological aspects / Plasma / Proteins / ras Proteins - metabolism / rho GTP-Binding Proteins - metabolism / rhoA GTP-Binding Protein / rhoC GTP-Binding Protein / Rodents / Science / Stromal Cells - cytology / Stromal Cells - physiology