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.
Bibliographical noteFunding 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).
© 2022, The Author(s).
- Inducible T-Cell Co-Stimulator Ligand/genetics
- Inducible T-Cell Co-Stimulator Protein/genetics
- Tertiary Lymphoid Structures