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It’s good to have Gremlins in the zone

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Science Immunology  04 Jun 2021:
Vol. 6, Issue 60, eabj7174
DOI: 10.1126/sciimmunol.abj7174

Abstract

A unique subset of Gremlin1-expressing fibroblastic reticular cells mediate cDC homeostasis and functionality within lymph nodes.

Immune cells are highly influenced by their local microenvironment, including the cytokine milieu and cross-talk with structural cells. The complex interactions between immune and structural cell subsets, including epithelial, endothelial, and stromal cells, are just beginning to be elucidated. Recent studies have found heterogeneous populations of stromal cells specialized in immune cell maintenance within secondary lymphoid organs, termed fibroblastic reticular cells (FRCs). Kapoor et al. substantially extend previous studies by further delineating FRC subsets in both mouse and human lymph nodes using single-cell RNA sequencing (scRNA-seq). Moreover, they utilize the power of mouse models to interrogate the specific function of a newly identified Gremlin1+ FRC subset in immune regulation.

Using scRNA-seq analysis of CD45 cells from lymph nodes in mice or humans, the authors identified two unique populations of stromal cells that express Grem1 (Gremlin1), further delineated as subsets of T cell zone FRCs. Next, using a tamoxifen-inducible Grem1 reporter [Grem1-CreERT2; Rosa26-LSL-eYFP] mouse model, Grem1-expressing FRCs were spatially localized within the T cell zone near the T-B border. Bulk RNA-seq and proteomics analyzes of Grem1+ and Grem1 FRCs revealed that Grem1+ cells were enriched for factors involved in immune cell cross-talk, such as homing cytokines CCL21 and CCL19. Most notably, depletion of Grem1-expressing cells via diphtheria toxin–inducible reporter [Grem1-CreERT2; Rosa26-LSL-eYFP/iDTR] led to a significant loss of CD11chi MHCIIinter resident dendritic cells and reduced cellularity of secondary lymphoid organs. However, the composition of the T and B lymphocyte compartments remained largely intact. Loss of resident DCs was due to decreased homeostatic proliferation in the absence of Grem1+ FRCs. In addition, Grem1 depletion resulted in reduced antigen-specific CD8 and CD4 T cell responses, linking the ability of Grem1+ FRC to maintain DC homeostasis with downstream alterations in adaptive immune function. Collectively, this study reiterates that interactions between immune cells and structural cells are closely intertwined and identifies a novel cell population that may be a therapeutic immunomodulatory target.

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