Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology.

Nayar, Saba, Campos, Joana, Smith, Charlotte G, Iannizzotto, Valentina, Gardner, David H, Mourcin, Frédéric, Roulois, David, Turner, Jason, Sylvestre, Marvin, Asam, Saba, Glaysher, Bridget, Bowman, Simon J, Fearon, Douglas T, Filer, Andrew, Tarte, Karin, Luther, Sanjiv A, Fisher, Benjamin A, Buckley, Christopher D, Coles, Mark C, Barone, Francesca (July 2019) Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. Proceedings of the National Academy of Sciences of USA, 116 (27). pp. 13490-13497. ISSN 0027-8424

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Abstract

Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.

Item Type:	Paper
Subjects:	diseases & disorders > immune system diseases > auto immune diseases diseases & disorders > cancer diseases & disorders diseases & disorders > immune system diseases Investigative techniques and equipment organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts Investigative techniques and equipment > flow cytometry organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immunofibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immunofibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immunofibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > tissues types and functions > Salivary Glands organs, tissues, organelles, cell types and functions > tissues types and functions
CSHL Authors:	Fearon, Douglas
Communities:	CSHL labs > Fearon lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	2 July 2019
Date Deposited:	06 May 2021 13:33
Last Modified:	26 Feb 2025 16:46
PMCID:	PMC6613169
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39996

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