Fibroblastic reticular cell lineage convergence in Peyer's patches governs intestinal immunity

Nat Immunol. 2021 Apr;22(4):510-519. doi: 10.1038/s41590-021-00894-5. Epub 2021 Mar 11.

Abstract

Fibroblastic reticular cells (FRCs) determine the organization of lymphoid organs and control immune cell interactions. While the cellular and molecular mechanisms underlying FRC differentiation in lymph nodes and the splenic white pulp have been elaborated to some extent, in Peyer's patches (PPs) they remain elusive. Using a combination of single-cell transcriptomics and cell fate mapping in advanced mouse models, we found that PP formation in the mouse embryo is initiated by an expansion of perivascular FRC precursors, followed by FRC differentiation from subepithelial progenitors. Single-cell transcriptomics and cell fate mapping confirmed the convergence of perivascular and subepithelial FRC lineages. Furthermore, lineage-specific loss- and gain-of-function approaches revealed that the two FRC lineages synergistically direct PP organization, maintain intestinal microbiome homeostasis and control anticoronavirus immune responses in the gut. Collectively, this study reveals a distinct mosaic patterning program that generates key stromal cell infrastructures for the control of intestinal immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication
  • Cell Lineage*
  • Cells, Cultured
  • Coronavirus Infections / immunology
  • Coronavirus Infections / metabolism
  • Coronavirus Infections / virology
  • Disease Models, Animal
  • Fibroblasts / immunology*
  • Fibroblasts / metabolism
  • Gastrointestinal Microbiome
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Host-Pathogen Interactions
  • Immunity, Mucosal*
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / virology
  • Intestine, Small / immunology*
  • Intestine, Small / metabolism
  • Intestine, Small / microbiology
  • Intestine, Small / virology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Murine hepatitis virus / immunology
  • Murine hepatitis virus / pathogenicity
  • Peyer's Patches / immunology*
  • Peyer's Patches / metabolism
  • Peyer's Patches / microbiology
  • Peyer's Patches / virology
  • Phenotype
  • Single-Cell Analysis
  • Transcriptome