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

• Published in: Nature immunology Vol. 22; no. 5; pp. 571 - 585
• Main Authors: Kapoor, Varun N., Müller, Sören, Keerthivasan, Shilpa, Brown, Markus, Chalouni, Cecile, Storm, Elaine E., Castiglioni, Alessandra, Lane, Ryan, Nitschke, Maximilian, Dominguez, Claudia X., Astarita, Jillian L., Krishnamurty, Akshay T., Carbone, Catherine B., Senbabaoglu, Yasin, Wang, Amber W., Wu, Xiumin, Cremasco, Viviana, Roose-Girma, Merone, Tam, Lucinda, Doerr, Jonas, Chen, Mark Z., Lee, Wyne P., Modrusan, Zora, Yang, Yeqing Angela, Bourgon, Richard, Sandoval, Wendy, Shaw, Andrey S., de Sauvage, Frederic J., Mellman, Ira, Moussion, Christine, Turley, Shannon J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2021; Nature Publishing Group
• Subjects: 631/250; 631/250/1620; 631/250/1620/1616; 631/250/1620/1826; 631/250/2152; Adaptive immunity; Aged; Animals; Apoptosis - genetics; Apoptosis - immunology; Biomedical and Life Sciences; Biomedicine; Cell junctions; Cell Proliferation - genetics; Cell Survival - genetics; Cell Survival - immunology; Dendritic cells; Dendritic Cells, Follicular - immunology; Dendritic Cells, Follicular - metabolism; Female; Fibroblasts - immunology; Fibroblasts - metabolism; Gene Expression Regulation - immunology; Gene Knock-In Techniques; Gremlin protein; Homeostasis; Humans; Immunity, Cellular - genetics; Immunology; Infectious Diseases; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Localization; Lymph nodes; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymphocytes; Lymphocytes T; Lymphoid tissue; Male; Mice; Mice, Transgenic; Niches; RNA-Seq; Single-Cell Analysis; Spleen; Stromal cells; Stromal Cells - immunology; Stromal Cells - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-021-00920-6

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. Fibroblastic reticular cells (FRCs) provide structural support and soluble factors necessary for proper lymph node organization and function. Turley and colleagues use scRNA-seq to identify a unique Gremlin1-expressing FRC subset that is found in T cell zones. Grem1 + FRCs support the survival of resident cDCs and are necessary to promote T cell immunity.