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

Research output: Contribution to journalArticle

Authors

  • Joana Dias De Campos
  • Charlotte Smith
  • Valentina Iannizzotto
  • Frédéric Mourcin
  • David Roulois
  • Marvin Sylvestre
  • Saba Asam
  • Bridget Glaysher
  • Simon J. Bowman
  • Douglas T. Fearon
  • Karin Tarte
  • Sanjiv A. Luther
  • Christopher Buckley
  • Mark C. Coles
  • Francesca Barone

External organisations

  • University Hospitals Birmingham NHS Trust
  • UMR INSERM U1236, Université Rennes 1, Etablissement Français du Sang, 35043 Rennes, France
  • University of York
  • University of Cambridge
  • University of Lausanne

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.

Details

Original languageEnglish
Article number201905301
Number of pages8
JournalProc. Natl. Acad. Sci. (USA)
Early online date18 Jun 2019
Publication statusE-pub ahead of print - 18 Jun 2019

Keywords

  • fibroblasts, Sjögren’s syndrome, autoimmunity, tertiary lymphoid structures