Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses

J Exp Med. 2014 Oct 20;211(11):2265-79. doi: 10.1084/jem.20132528. Epub 2014 Oct 13.

Abstract

Fibroblast-like cells of secondary lymphoid organs (SLO) are important for tissue architecture. In addition, they regulate lymphocyte compartmentalization through the secretion of chemokines, and participate in the orchestration of appropriate cell-cell interactions required for adaptive immunity. Here, we provide data demonstrating the functional importance of SLO fibroblasts during Notch-mediated lineage specification and immune response. Genetic ablation of the Notch ligand Delta-like (DL)1 identified splenic fibroblasts rather than hematopoietic or endothelial cells as niche cells, allowing Notch 2-driven differentiation of marginal zone B cells and of Esam(+) dendritic cells. Moreover, conditional inactivation of DL4 in lymph node fibroblasts resulted in impaired follicular helper T cell differentiation and, consequently, in reduced numbers of germinal center B cells and absence of high-affinity antibodies. Our data demonstrate previously unknown roles for DL ligand-expressing fibroblasts in SLO niches as drivers of multiple Notch-mediated immune differentiation processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Biomarkers / metabolism
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules / metabolism
  • Cell Differentiation
  • Cellular Microenvironment / immunology*
  • Chemokine CCL19 / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Fibroblasts / metabolism*
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • Immunity*
  • Immunophenotyping
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Lymphoid Tissue / immunology*
  • Lymphoid Tissue / metabolism*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Phenotype
  • Receptors, Notch / metabolism*
  • Spleen / immunology
  • Spleen / metabolism
  • Stromal Cells / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules
  • Chemokine CCL19
  • DLL4 protein, mouse
  • Dlk1 protein, mouse
  • Esam protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Notch