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

Abstract

ABSTRACTBackgroundHLA-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 (IFNγ),Borrelia burgdorferi, and/orB. burgdorferipeptidoglycan (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 patientsin situ.MHC class II and costimulatory molecules were expressed by FLS followingin vitrostimulation with IFNγ andB. burgdorferiand 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 naïve OT-II CD4+ T cells, particularly when FLS were stimulated with both IFNγ 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 IFNγ-activated MHC-II+ fibroblast-like synoviocytes (FLS) stimulated withBorrelia burgdorferipresent foreign and self MHC-II antigens, including Lyme autoantigens. Furthermore, IFNγ-activated MHC-II+ FLS stimulated withB. burgdorferipeptidoglycan can induce activation and proliferation of naïve CD4+ T cells in an MHC-II antigen-dependent manner, demonstrating that activated MHC-II+ FLS are inducible antigen presenting cells.