TY - JOUR
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 - © 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
U2 - 10.1038/s42003-022-03344-6
DO - 10.1038/s42003-022-03344-6
M3 - Article
C2 - 35508704
VL - 5
SP - 413
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
ER -