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Updated: Jan 23, 2026

Visualizing Lymph Node Structure and Cellular Localization using Ex-Vivo Confocal Microscopy
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Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology

Saba Nayar1,2, Joana Campos1,2, Charlotte G Smith1,2

  • 1Rheumatoid 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.

Proceedings of the National Academy of Sciences of the United States of America
|June 20, 2019
PubMed

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.

Keywords:
Sjögren’s syndromeautoimmunityfibroblaststertiary lymphoid structures

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