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

Saba Nayar (1, 2) , Joana Campos (1, 2) , Charlotte G Smith (1, 2) , Valentina Iannizzotto (1, 2) , David H Gardner (1, 2) , Frédéric Mourcin (3) , David Roulois (3) , Jason Turner (1, 2) , Marvin Sylvestre (3) , Saba Asam (1, 2) , Bridget Glaysher (4) , Simon J Bowman (1, 2) , Douglas T Fearon (5) , Andrew Filer (1, 2) , Karin Tarte (3) , Sanjiv A Luther (6) , Benjamin A Fisher (1, 2) , Christopher D Buckley (1, 2) , Mark C Coles (4) , Francesca Barone (1, 2)

1 Queens Elizabeth Hospital [Birmingham]
2 University of Birmingham [Birmingham]
3 MICMAC - Microenvironment, Cell Differentiation, Immunology and Cancer
4 University of York [York, UK]
5 CAM - University of Cambridge [UK]
6 UNIL - Université de Lausanne = University of Lausanne

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 para-crine 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 lympho-toxin. 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. © 2019 National Academy of Sciences. All rights reserved.

Keywords: Tertiary lymphoid; Structures; Sjögren’s syndrome; Fibroblasts; Autoimmunity

Domains: Life Sciences [q-bio]; Cancer

Saba Nayar, Joana Campos, Charlotte G Smith, Valentina Iannizzotto, David H Gardner, et al.. Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (27), pp.13490-13497. ⟨10.1073/pnas.1905301116⟩. ⟨hal-02182036⟩