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

Abstract

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-CreER^T2 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.