Direct tissue-sensing reprograms TLR4+ Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients

• DOI: 10.1038/s42003-021-02659-0
• Publication Date: 2021-09-27T10:20:00Z
• Authors: Daniela Amaral-Silva; Rute Gonçalves; Rita C. Torrão; Rita Torres; Sandra Falcão; Maria João Gonçalves; Maria Paula Araújo; Maria José Martins; Carina Lopes; Agna Neto; José Marona; Tiago Costa; Walter Castelão; Ana Bento Silva; Inês Silva; Maria Helena Lour...; Margarida Mateus; Nuno Pina Gonçalves; Santiago Manica; Manuela Costa; Fernando M. Pimen...; Ana Filipa Mourão; Jaime C. Branco; Helena Soares
• Keywords: Male; 0301 basic medicine; 0303 health sciences; QH301-705.5; T-Lymphocytes; Middle Aged; Article; 3. Good health; Arthritis, Rheumatoid; Toll-Like Receptor 4; 03 medical and health sciences; Synovial Fluid; Humans; Female; Biology (General); Aged

AbstractCD4+ 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.