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

Nayar S; Campos J; Smith CG; Iannizzotto V; Gardner DH; Mourcin F; Roulois D; Turner J; Sylvestre M; Asam S; Glaysher B; Bowman SJ; Fearon DT; Filer A; Tarte K; Luther SA; Fisher BA; Buckley CD; Coles MC; Barone F

doi:10.1073/pnas.1905301116

Back

Journal article

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

Nayar S Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Campos J Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Smith CG Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Iannizzotto V Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Gardner DH Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Mourcin F UMR INSERM U1236, Université Rennes 1, Etablissement Français du Sang, 35043 Rennes, France.
Roulois D UMR INSERM U1236, Université Rennes 1, Etablissement Français du Sang, 35043 Rennes, France.
Turner J Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Sylvestre M UMR INSERM U1236, Université Rennes 1, Etablissement Français du Sang, 35043 Rennes, France.
Asam S Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Glaysher B Centre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, YO10 5DD York, United Kingdom.
Bowman SJ Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Fearon DT Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, CB2 0RE Cambridge, United Kingdom.
Filer A Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Tarte K UMR INSERM U1236, Université Rennes 1, Etablissement Français du Sang, 35043 Rennes, France.
Luther SA Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, 1066 Epalinges, Switzerland.
Fisher BA Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Buckley CD Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom.
Coles MC Centre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, YO10 5DD York, United Kingdom; f.barone@bham.ac.uk mark.coles@kennedy.ox.ac.uk.
Barone F Rheumatoid Arthritis Pathogenesis Centre of Excellence, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, B15 2WB Birmingham, United Kingdom; f.barone@bham.ac.uk mark.coles@kennedy.ox.ac.uk.

2019-06-20

Published in:

Proceedings of the National Academy of Sciences of the United States of America. - 2019

Fluorescent Antibody Technique

English 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.

Language