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

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 Lourenço, Margarida Mateus, Nuno Pina Gonçalves, Santiago Manica, Manuela CostaFernando M. Pimentel-Santos, Ana Filipa Mourão, Jaime C. Branco, Helena Soares

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Article number1135
JournalCommunications Biology
Volume4
Issue number1
DOIs
Publication statusPublished - 27 Sep 2021

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