Dendritic cells control fibroblastic reticular network tension and lymph node expansion

Nature. 2014 Oct 23;514(7523):498-502. doi: 10.1038/nature13814.

Abstract

After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph node cellularity, leading to organ expansion. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actomyosin / metabolism
  • Animals
  • Cell Membrane / metabolism
  • Cytoskeleton / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / physiology*
  • Female
  • Fibroblasts / cytology*
  • Fibroblasts / physiology
  • Inflammation / immunology
  • Lectins, C-Type / metabolism
  • Lymph Nodes / cytology*
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Male
  • Membrane Glycoproteins / metabolism
  • Mice
  • Stromal Cells / cytology*
  • Stromal Cells / physiology
  • ras Proteins / metabolism
  • rho GTP-Binding Proteins / metabolism
  • rhoC GTP-Binding Protein

Substances

  • CLEC-2 protein, mouse
  • Gp38 protein, mouse
  • Lectins, C-Type
  • Membrane Glycoproteins
  • Actomyosin
  • RhoA protein, mouse
  • Rhoc protein, mouse
  • ras Proteins
  • rho GTP-Binding Proteins
  • rhoC GTP-Binding Protein