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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)413
JournalCommunications Biology
Volume5
Issue number1
DOIs
Publication statusPublished - 4 May 2022

Bibliographical note

© 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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