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. In order to identify how the synovial microenvironment impinges on CD4+ T cells pathogenic functions in Rheumatoid Arthritis (RA), Amaral-Silva examined RA patient blood and synovial fluif and identified the presence of a TLR4+ follicular helper T (Tfh) cell-like population. They provided mechanistic insight into how TLR4(+) T cells uniquely reconcile an ability to promote systemic antibody production with a local synovial driven-tissue damage program.