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. Mechanistically, we unveiled that homotypic T-T cell interactions through non-cognate HLA-DR:TCR contacts regulate TLR4 expression on T cells. TLR4 + T cells possess a two-pronged pathogenic activity. Upon TCR and ICOS engagement, TLR4 + T cells produce IL-21, a cytokine known to sponsor antibody production. However, direct TLR4 + engagement on T cells, by endogenous ligands in the arthritic joint, reprograms them towards an IL-17 inflammatory profile compatible with tissue damage program. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Ex vivo, synovial fluid TLR4 + T cells produced IL-17, but not IL-21. TLR4 + T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program. TLR4 + T cells could constitute an attractive cellular target and predictive biomarker for erosive arthritis.