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FLS\u2010derived extracellular matrix (ECM) proteins, including fibronectin\u20101 (FN1), contain immunogenic CD4+ T cell epitopes in patients with postinfectious Lyme arthritis (LA). However, the role of FLS in presentation of these T cell epitopes remains uncertain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Primary LA FLS and primary murine FLS stimulated with interferon gamma (IFN\u03b3), <jats:italic>Borrelia burgdorferi<\/jats:italic>, and\/or <jats:italic>B burgdorferi<\/jats:italic> peptidoglycan (PG) were assessed for properties associated with antigen presentation. HLA\u2010DR\u2013presented peptides from stimulated LA FLS were identified by immunopeptidomics analysis. OT\u2010II T cells were co\u2010cultured with stimulated murine FLS in the presence of cognate ovalbumin antigen to determine the potential of FLS to act as inducible antigen presenting cells (APCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>FLS expressed HLA\u2010DR molecules within inflamed synovial tissue and tendons from patients with postinfectious LA in situ. Major histocompatibility complex (MHC) class II and co\u2010stimulatory molecules were expressed by FLS following in vitro stimulation with IFN\u03b3 and <jats:italic>B burgdorferi<\/jats:italic> and presented both foreign and self\u2010MHC\u2010II peptides, including an immunogenic T cell epitope derived from Lyme autoantigen FN1. Stimulated FLS induced proliferation of naive OT\u2010II CD4+ T cells that were dependent on OT\u2010II antigen and CD40. Stimulation with <jats:italic>B burgdorferi<\/jats:italic> PG enhanced FLS\u2010mediated T cell activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>MHC\u2010II+ FLS are inducible APCs that can induce CD4+ T cell activation in an antigen\u2010 and CD40\u2010dependent manner. Activated FLS can also present ECM\u2010derived Lyme autoantigens, implicating FLS in amplifying tissue\u2010localized autoimmunity in LA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acr2.11710","type":"journal-article","created":{"date-parts":[[2024,7,27]],"date-time":"2024-07-27T23:39:47Z","timestamp":1722123587000},"page":"678-689","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["<scp>HLA<\/scp>\u2010<scp>DR<\/scp>\u2013Expressing Fibroblast\u2010Like Synoviocytes Are Inducible Antigen Presenting Cells That Present Autoantigens in Lyme Arthritis"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8675-904X","authenticated-orcid":false,"given":"Joseph R.","family":"Rouse","sequence":"first","affiliation":[{"name":"Medical College of Wisconsin  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