Author(s):
Amaral-Silva, Daniela ; Gonçalves, Rute ; Torrão, Rita C. ; Torres, Rita ; Falcão, Sandra ; Gonçalves, Maria João ; Araújo, Maria Paula ; Martins, Maria José ; Lopes, Carina ; Neto, Agna ; Marona, José ; Costa, Tiago ; Castelão, Walter ; Silva, Ana Bento ; Silva, Inês ; Lourenço, Maria Helena ; Mateus, Margarida ; Gonçalves, Nuno Pina ; Manica, Santiago ; Costa, Manuela ; Pimentel-Santos, F. M. ; Mourão, Ana Filipa ; Branco, Jaime ; Soares, Helena
Date: 2021
Persistent ID: http://hdl.handle.net/10362/127059
Origin: Repositório Institucional da UNL
Subject(s): Medicine (miscellaneous); Biochemistry, Genetics and Molecular Biology(all); Agricultural and Biological Sciences(all)
Description
Funding Information: We thank Cláudia Andrade for technical support and Juliana Gonçalves for testing samples for SARS-CoV-2 exposure. We are extremely grateful to all the participants of the study and to the whole rheumatology department at Hospital Egas Moniz that made this study possible. This work was supported by Fundação para a Ciência e Tecnologia (FCT) PTDC/MEC-REU/29520/2017, by iNOVA4Health UID/Multi/04462 and by Portuguese Society for Rheumatology (SPR) grants to H.S. H.S. is supported by FCT through IF/01722/2013 and CEECIND/01049/2020, DAS and RCT were supported by FCT through PD/BD/137409/2018 and UID/Multi/04462, respectively. Publisher Copyright: © 2021, The Author(s).
CD4+ T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4+ T cells pathogenic functions. Here, we identified a TLR4+ follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. TLR4+ T cells possess a two-pronged pathogenic activity whereby direct TLR4+ engagement by endogenous ligands in the arthritic joint reprograms them from an IL-21 response, known to sponsor antibody production towards an IL-17 inflammatory program recognized to fuel tissue damage. Ex vivo, synovial fluid TLR4+ T cells produced IL-17, but not IL-21. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Mechanistically, we unveiled that T-cell HLA-DR regulates their TLR4 expression. TLR4+ T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program.
