biostudies-literatureRomoff MRNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institute of Allergy and Infectious DiseasesNIAID NIH HHSNHGRI NIH HHSNIAMS NIH HHSNational Institute of General Medical SciencesNational Human Genome Research InstituteNIGMS NIH HHSe193054https://www.ebi.ac.uk/biostudies/studies/S-EPMC12643496biostudies-literatureUnknown10(22)In the rheumatoid arthritis (RA) synovium, resident fibroblast-like synoviocytes (FLS) express MHC class II molecules (HLA-D) but lack the costimulatory signals typically required for T cell activation. Here, we demonstrate that antigen presentation by FLS induces a distinct T cell activation state characterized by high CD69 yet reduced CD25 and HLA-DR expression, suppressed proliferation, and decreased effector cytokine production compared with professional antigen-presenting cells (APCs), such as macrophages. FLS were also capable of suppressing macrophage-induced T cell activation, underscoring their dominant immunomodulatory role in the synovial microenvironment. Mechanistically, we identify indoleamine 2,3-dioxygenase-mediated (IDO1-mediated) tryptophan depletion as the primary driverJCI insightRheumatoid arthritis synovial fibroblasts modulate T cell activation.PMC12643496AI034206-28U01 HG012103R37 AI034206T32 AR071302T32 5T32AR071302-04R01 AI148435R01 AI034206AI148435T32GM152349T32 GM152349Smith MHDiCarlo EFPeriyakoil PKRamirez DLeslie CSGoodman SMDonlin LTRudensky AYRomoff MRfalseRheumatoid arthritis synovial fibroblasts modulate T cell activation.In the rheumatoid arthritis (RA) synovium, resident fibroblast-like synoviocytes (FLS) express MHC class II molecules (HLA-D) but lack the costimulatory signals typically required for T cell activation. Here, we demonstrate that antigen presentation by FLS induces a distinct T cell activation state characterized by high CD69 yet reduced CD25 and HLA-DR expression, suppressed proliferation, and decreased effector cytokine production compared with professional antigen-presenting cells (APCs), such as macrophages. FLS were also capable of suppressing macrophage-induced T cell activation, underscoring their dominant immunomodulatory role in the synovial microenvironment. Mechanistically, we identify indoleamine 2,3-dioxygenase-mediated (IDO1-mediated) tryptophan depletion as the primary driver2025-01-01T00:00:00Z2025 Nov2026-06-05T18:41:07.573Z2026-05-20T03:13:32.917ZS-EPMC126434964105595410.1172/jci.insight.193054