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

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.