HLA-DR-expressing fibroblast-like synoviocytes are inducible antigen presenting cells that present autoantigens in Lyme arthritis

Abstract

BackgroundHLA-DR-expressing fibroblast-like synoviocytes (FLS) are a prominent cell type in synovial tissue in chronic inflammatory forms of arthritis. We recently showed that peptides from several extracellular matrix (ECM) proteins, including fibronectin-1 (FN1), contained 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. MethodsPrimary LA FLS and primary murine FLS stimulated with interferon gamma (IFN{gamma}), Borrelia burgdorferi, and/or B. burgdorferi peptidoglycan (PG) were assessed for properties associated with antigen presentation. HLA-DR-presented peptides from stimulated LA FLS were identified by immunopeptidomics analysis. OT-II T cells were cocultured with stimulated murine FLS in the presence of cognate ovalbumin antigen to determine the potential of FLS to act as inducible antigen presenting cells (APC). ResultsFLS expressed HLA-DR molecules within inflamed synovial tissue and tendons from patients with post-infectious LA patients in situ. MHC class II and costimulatory molecules were expressed by FLS following in vitro stimulation with IFN{gamma} and B. burgdorferi and presented both foreign and self MHC-II peptides, including T cell epitopes derived from two Lyme autoantigens fibronectin-1 (FN1) and endothelial cell growth factor (ECGF). Stimulated murine FLS induced proliferation of naive OT-II CD4+ T cells, particularly when FLS were stimulated with both IFN{gamma} and PG. ConclusionsMHC-II+ FLS are inducible APCs that can induce CD4+ T cell activation and can present Lyme autoantigens derived from ECM proteins, thereby amplifying tissue-localized autoimmune CD4+ T cell responses in LA. AUTHORS SUMMARYThis study demonstrates that IFN{gamma}-activated MHC-II+ fibroblast-like synoviocytes (FLS) stimulated with Borrelia burgdorferi present foreign and self MHC-II antigens, including Lyme autoantigens. Furthermore, IFN{gamma}-activated MHC-II+ FLS stimulated with B. burgdorferi peptidoglycan can induce activation and proliferation of naive CD4+ T cells in an MHC-II antigen-dependent manner, demonstrating that activated MHC-II+ FLS are inducible antigen presenting cells.