Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction

Saba Nayar; Elena Pontarini; Joana Campos; Onorina Berardicurti; Charlotte G Smith; Saba Asam; David H Gardner; Serena Colafrancesco; Davide Lucchesi; Rachel Coleby; Ming-May Chung; Valentina Iannizzotto; Kelly Hunter; Simon J Bowman; Gianluca Carlesso; Ronald Herbst; Helen M McGettrick; Jeff Browning; Christopher D Buckley; Benjamin A Fisher; Michele Bombardieri; Francesca Barone

doi:10.1038/s42003-022-03344-6

Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction

Saba Nayar, Elena Pontarini, Joana Campos, Onorina Berardicurti, Charlotte G Smith, Saba Asam, David H Gardner, Serena Colafrancesco, Davide Lucchesi, Rachel Coleby, Ming-May Chung, Valentina Iannizzotto, Kelly Hunter, Simon J Bowman, Gianluca Carlesso, Ronald Herbst, Helen M McGettrick, Jeff Browning, Christopher D Buckley, Benjamin A FisherMichele Bombardieri, Francesca Barone

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Abstract

Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans.

Original language	English
Article number	413
Journal	Communications Biology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s42003-022-03344-6
Publication status	Published - 4 May 2022

Bibliographical note

Funding Information:
We thank David Withers and Jorge Caamano for providing animals; Technology Hub (University of Birmingham) for flow cytometry, imaging, and PCR and Birmingham Tissue Analytics (University of Birmingham) for assistance with RNAscope analysis. We are indebted to the Biomedical Services Unit and Biological Services Facility for maintaining the colonies. F.B. was funded by Versus Arthritis Senior Fellow. C.D.B. was supported by Versus Arthritis Grant (G0601156), S.N., B.A.F. and S.J.B. have received support from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (Grant BRC-1215-20009). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. H.M.M. was supported by an Arthritis Research Career Development Fellowship (19899).

Publisher Copyright:
© 2022, The Author(s).

Keywords

Animals
Chemokines
Inducible T-Cell Co-Stimulator Ligand/genetics
Inducible T-Cell Co-Stimulator Protein/genetics
Inflammation
Mice
Tertiary Lymphoid Structures

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Nayar, S., Pontarini, E., Campos, J., Berardicurti, O., Smith, C. G., Asam, S., Gardner, D. H., Colafrancesco, S., Lucchesi, D., Coleby, R., Chung, M-M., Iannizzotto, V., Hunter, K., Bowman, S. J., Carlesso, G., Herbst, R., McGettrick, H. M., Browning, J., Buckley, C. D., ... Barone, F. (2022). Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction. Communications Biology, 5(1), Article 413. https://doi.org/10.1038/s42003-022-03344-6

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title = "Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction",

abstract = "Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans.",

keywords = "Animals, Chemokines, Inducible T-Cell Co-Stimulator Ligand/genetics, Inducible T-Cell Co-Stimulator Protein/genetics, Inflammation, Mice, Tertiary Lymphoid Structures",

author = "Saba Nayar and Elena Pontarini and Joana Campos and Onorina Berardicurti and Smith, {Charlotte G} and Saba Asam and Gardner, {David H} and Serena Colafrancesco and Davide Lucchesi and Rachel Coleby and Ming-May Chung and Valentina Iannizzotto and Kelly Hunter and Bowman, {Simon J} and Gianluca Carlesso and Ronald Herbst and McGettrick, {Helen M} and Jeff Browning and Buckley, {Christopher D} and Fisher, {Benjamin A} and Michele Bombardieri and Francesca Barone",

note = "Funding Information: We thank David Withers and Jorge Caamano for providing animals; Technology Hub (University of Birmingham) for flow cytometry, imaging, and PCR and Birmingham Tissue Analytics (University of Birmingham) for assistance with RNAscope analysis. We are indebted to the Biomedical Services Unit and Biological Services Facility for maintaining the colonies. F.B. was funded by Versus Arthritis Senior Fellow. C.D.B. was supported by Versus Arthritis Grant (G0601156), S.N., B.A.F. and S.J.B. have received support from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (Grant BRC-1215-20009). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. H.M.M. was supported by an Arthritis Research Career Development Fellowship (19899). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s42003-022-03344-6",

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Nayar, S, Pontarini, E, Campos, J, Berardicurti, O, Smith, CG, Asam, S, Gardner, DH, Colafrancesco, S, Lucchesi, D, Coleby, R, Chung, M-M, Iannizzotto, V, Hunter, K, Bowman, SJ, Carlesso, G, Herbst, R, McGettrick, HM, Browning, J, Buckley, CD, Fisher, BA, Bombardieri, M & Barone, F 2022, 'Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction', Communications Biology, vol. 5, no. 1, 413. https://doi.org/10.1038/s42003-022-03344-6

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T1 - Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction

AU - Nayar, Saba

AU - Pontarini, Elena

AU - Campos, Joana

AU - Berardicurti, Onorina

AU - Smith, Charlotte G

AU - Asam, Saba

AU - Gardner, David H

AU - Colafrancesco, Serena

AU - Lucchesi, Davide

AU - Coleby, Rachel

AU - Chung, Ming-May

AU - Iannizzotto, Valentina

AU - Hunter, Kelly

AU - Bowman, Simon J

AU - Carlesso, Gianluca

AU - Herbst, Ronald

AU - McGettrick, Helen M

AU - Browning, Jeff

AU - Buckley, Christopher D

AU - Fisher, Benjamin A

AU - Bombardieri, Michele

AU - Barone, Francesca

N1 - Funding Information: We thank David Withers and Jorge Caamano for providing animals; Technology Hub (University of Birmingham) for flow cytometry, imaging, and PCR and Birmingham Tissue Analytics (University of Birmingham) for assistance with RNAscope analysis. We are indebted to the Biomedical Services Unit and Biological Services Facility for maintaining the colonies. F.B. was funded by Versus Arthritis Senior Fellow. C.D.B. was supported by Versus Arthritis Grant (G0601156), S.N., B.A.F. and S.J.B. have received support from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (Grant BRC-1215-20009). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. H.M.M. was supported by an Arthritis Research Career Development Fellowship (19899). Publisher Copyright: © 2022, The Author(s).

PY - 2022/5/4

Y1 - 2022/5/4

N2 - Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans.

AB - Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans.

KW - Animals

KW - Chemokines

KW - Inducible T-Cell Co-Stimulator Ligand/genetics

KW - Inducible T-Cell Co-Stimulator Protein/genetics

KW - Inflammation

KW - Mice

KW - Tertiary Lymphoid Structures

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DO - 10.1038/s42003-022-03344-6

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JO - Communications Biology

JF - Communications Biology

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ER -

Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction

Abstract

Bibliographical note

Keywords

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