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

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Significance

TLS, which are clusters of lymphocytes and stromal cells observed at sites of chronic inflammation, play a key role in sustaining disease progression in autoimmune conditions. While the role of lymphocytes in these structures has been studied extensively, the role of fibroblasts, nonhematopoietic stromal cells, in the formation and maintenance of TLS has not been demonstrated. Here, we establish that, at sites of TLS establishment, resident fibroblasts expand and acquire immunological features in a process that is dependent on IL13 and IL22. Interference with this process or depletion of immunofibroblasts leads to involution of TLS, resulting in decreased immune-cell activation and resolution of tissue pathology, thus supporting the use of fibroblast-targeting strategies to treat TLS-associated autoimmune diseases.

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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Most cited references 35

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Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha.

Matthew Kraman, Paul J Bambrough, James Arnold … (2010)

The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.

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IL-13 effector functions.

Thomas Wynn (2003)

IL-13 was first recognized for its effects on B cells and monocytes, where it upregulated class II expression, promoted IgE class switching and inhibited inflammatory cytokine production. It was also thought to be functionally redundant with IL-4. However, studies conducted with knockout mice, neutralizing antibodies, and novel antagonists demonstrate that IL-13 possesses several unique effector functions that distinguish it from IL-4. Resistance to most gastrointestinal nematodes is mediated by type-2 cytokine responses, in which IL-13 plays a dominant role. By regulating cell-mediated immunity, IL-13 modulates resistance to intracellular organisms including Leishmania major, Leishmania mexicana, and Listeria monocytogenes. In the lung, IL-13 is the central mediator of allergic asthma, where it regulates eosinophilic inflammation, mucus secretion, and airway hyperresponsiveness. Manipulation of IL-13 effector function may also prove useful in the treatment of some cancers like B-cell chronic lymphocytic leukemia and Hodgkin's disease, where IL-13 modulates apoptosis or tumor cell growth. IL-13 can also inhibit tumor immunosurveillance. As such, inhibitors of IL-13 might be effective as cancer immunotherapeutics by boosting type-1-associated anti-tumor defenses. Finally, IL-13 was revealed as a potent mediator of tissue fibrosis in both schistosomiasis and asthma, which indicates that it is a key regulator of the extracellular matrix. The mechanisms that regulate IL-13 production and/or function have also been investigated, and IL-4, IL-12, IL-18, IFN-gamma, IL-10, TGF-beta, TNF-alpha, and the IL-4/IL-13 receptor complex play important roles. This review highlights the effector functions of IL-13 and describes multiple pathways for modulating its activity in vivo.

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Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity

Sanjiv A. Luther, Lauren B Rodda, Erick Lu … (2018)

Stromal cells (SCs) establish the compartmentalization of lymphoid tissues critical to the immune response. However, the full diversity of lymph node (LN) SCs remains undefined. Using droplet-based single-cell RNA sequencing, we identified nine peripheral LN non-endothelial SC clusters. Included are the established subsets, Ccl19 hi T-zone reticular cells (TRCs), marginal reticular cells, follicular dendritic cells (FDCs), and perivascular cells. We also identified Ccl19 lo TRCs, likely including cholesterol-25-hydroxylase + cells located at the T-zone perimeter, Cxcl9 + TRCs in the T-zone and interfollicular region, CD34 + SCs in the capsule and medullary vessel adventitia, indolethylamine N-methyltransferase + SCs in the medullary cords, and Nr4a1 + SCs in several niches. These data help define how transcriptionally distinct LN SCs support niche-restricted immune functions and provide evidence that many SCs are in an activated state. In Brief: Lymph node stromal cells support diverse processes, but bulk assessments obscure their niche-specific functions. Rodda et al. identify transcriptional profiles for nine lymph node stromal cell clusters using single-cell RNA sequencing, validate subset markers in situ , and suggest niche-restricted functions.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 2 July 2019

Publication date (Electronic): 18 June 2019

Publication date PMC-release: 18 June 2019

Volume: 116

Issue: 27

Pages: 13490-13497

Affiliations

[1] ^aRheumatoid 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;

[2] ^bbNIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust , University of Birmingham, B15 2TT, Birmingham, UK;

[3] ^cUMR INSERM U1236, Université Rennes 1 , Etablissement Français du Sang, 35043 Rennes, France;

[4] ^dCentre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York , YO10 5DD York, United Kingdom;

[5] ^eCancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge , CB2 0RE Cambridge, United Kingdom;

[6] ^fDepartment of Biochemistry, Center of Immunity and Infection, University of Lausanne , 1066 Epalinges, Switzerland

Author notes

³To whom correspondence may be addressed. Email: f.barone@ 123456bham.ac.uk or mark.coles@ 123456kennedy.ox.ac.uk .

Edited by Jason G. Cyster, University of California, San Francisco, CA, and approved May 16, 2019 (received for review April 10, 2019)

Author contributions: S.N., K.T., S.A.L., B.A.F., C.D.B., M.C.C., and F.B. designed research; S.N., J.C., C.G.S., V.I., D.H.G., F.M., D.R., J.T., M.S., S.A., B.G., S.J.B., A.F., and K.T. performed research; D.T.F. contributed new reagents/analytic tools; S.N., J.C., and F.B. analyzed data; and S.N. and F.B. wrote the paper.

¹S.N. and J.C. contributed equally to this work.

²Present address: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7FY, United Kingdom.