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Cited by 203T-cell and B-cell ImmunologyIL-33, ST2, and ILC PathwaysCancer Immunotherapy and Biomarkers

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

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Nayar, Saba, Campos, Joana, Smith, Charlotte G., Iannizzotto, Valentina, Gardner, David H., Mourcin, Frédéric, Roulois, David, Turner, Jason +12 more·2019·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1905301116PMC PMC6613169
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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.

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  • Single-cell sequencing indicates common traits are preserved across tissues and species.

    “While single-cell sequencing indicates common traits are preserved49–51, it will become increasingly pressing to define common and specific effects of CAFs.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [51]

    The Discussion (page not available) describes immunofibroblast networks in humans and a mouse model as phenotypically and functionally similar to networks in secondary lymphoid organs. But the Results describe single-cell PCR in human salivary-gland fibroblasts, not single-cell sequencing demonstrating preserved traits across tissues and species; the Discussion also notes differences between murine and human fibroblasts. (LLM, conf=0.83)

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Authors
Nayar, S., Campos, J., Smith, C. G., Iannizzotto, V., Gardner, D. H., Mourcin, F., Roulois, D., Turner, J., Sylvestre, M., Asam, S., Glaysher, B., Bowman, S. J., Fearon, D. T., Filer, A., Tarte, K., Luther, S. A., Fisher, B. A., Buckley, C. D., Coles, M. C., & Barone, F.
Affiliations
  • University Hospitals Birmingham NHS Foundation Trust (GB)
  • Inserm (FR)
  • University of York (GB)
  • University of Cambridge (GB)
  • University of Lausanne (CH)
Corresponding author
  • Coles, Mark C.
  • Barone, Francesca
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2019-06-18
Volume
116
Issue
27
Pages
13490-13497
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1905301116
PMC
PMC6613169
OpenAlex
W2949851288
Cited by
203
References
2
Citations by year
2026: 26 · 2025: 38 · 2024: 27 · 2023: 24 · 2022: 29 · 2021: 26 · 2020: 25 · 2019: 7
FWCI
8.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, cc-by-nc-nd)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
  • IRIS (submittedVersion, cc-by-nc-nd)
  • HAL (submittedVersion, other-oa)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc-nd)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
Funders
  • Versus Arthritis (21236)
  • DH | National Institute for Health Research (000)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
tertiary lymphoid structures, podoplanin, stromal cell differentiation, IL-13, IL-22, lymphotoxin, paracrine signaling, autocrine signaling, lymphocyte recruitment, mucosal inflammation
MeSH terms
Tertiary Lymphoid Structures, Interleukin-22, Animals, Disease Models, Animal, Fibroblasts, Flow Cytometry, Fluorescent Antibody Technique, Humans, Interleukins, Lymphocytes, Salivary Glands, Interleukin-13, Mice

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