Gremlin 1+ fibroblastic niche maintains dendritic cell homeostasis in lymphoid tissues

Nat Immunol. 2021 May;22(5):571-585. doi: 10.1038/s41590-021-00920-6. Epub 2021 Apr 26.


Fibroblastic reticular cells (FRCs) are specialized stromal cells that define tissue architecture and regulate lymphocyte compartmentalization, homeostasis, and innate and adaptive immunity in secondary lymphoid organs (SLOs). In the present study, we used single-cell RNA sequencing (scRNA-seq) of human and mouse lymph nodes (LNs) to identify a subset of T cell-zone FRCs defined by the expression of Gremlin1 (Grem1) in both species. Grem1-CreERT2 knock-in mice enabled localization, multi-omics characterization and genetic depletion of Grem1+ FRCs. Grem1+ FRCs primarily localize at T-B cell junctions of SLOs, neighboring pre-dendritic cells and conventional dendritic cells (cDCs). As such, their depletion resulted in preferential loss and decreased homeostatic proliferation and survival of resident cDCs and compromised T cell immunity. Trajectory analysis of human LN scRNA-seq data revealed expression similarities to murine FRCs, with GREM1+ cells marking the endpoint of both trajectories. These findings illuminate a new Grem1+ fibroblastic niche in LNs that functions to maintain the homeostasis of lymphoid tissue-resident cDCs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Aged
  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology
  • Cell Proliferation / genetics
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Dendritic Cells, Follicular / immunology*
  • Dendritic Cells, Follicular / metabolism
  • Female
  • Fibroblasts / immunology*
  • Fibroblasts / metabolism
  • Gene Expression Regulation / immunology
  • Gene Knock-In Techniques
  • Humans
  • Immunity, Cellular / genetics
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology*
  • Male
  • Mice
  • Mice, Transgenic
  • RNA-Seq
  • Single-Cell Analysis
  • Stromal Cells / immunology*
  • Stromal Cells / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism


  • GREM1 protein, human
  • Grem1 protein, mouse
  • Intercellular Signaling Peptides and Proteins