T-cell-derived Exosomal Proteins ECP and BPI Induce Cytokines and Tissue Inflammation in Systemic Lupus Erythematosus

Abstract

Abstract T cells play critical roles in the pathogenesis of systemic lupus erythematosus (SLE). Serum-derived exosomes are increased in human SLE patients and are correlated with disease severity; however, the property of T-cell-derived exosomes from SLE patients remains unclear. We characterized proteins of SLE T cell-derived exosomes by exosome MACSPlex analysis and proteomics using T-cell supernatants from human SLE patients and healthy controls. We identified two exosoaml proteins, eosinophil cationic protein (ECP, also named human RNase 3) and bactericidal/permeability-increasing protein (BPI), which were overexpressed in SLE T-cell-derived exosomes and T cells. Both T-cell-specific ECP transgenic (Lck-ECP Tg) and BPI transgenic (Lck-BPI Tg) mice displayed multi-tissue inflammation. Lck-ECP and Lck-BPI Tg mice displayed early induction of serum IFN-γ levels and IL-1β levels, respectively. Single-cell RNA sequencing (scRNA-seq) showed the induction of IFN-γ mRNA and inflammatory pathways in ECP Tg T cells. ScRNA-seq also showed the reduction of Treg population in BPI Tg T cells; conversely, Treg differentiation was enhanced by BPI knockout. Remarkably, adoptively transferred ECP-containing or BPI-containing exosomes stimulated serum autoantibodies levels and induced nephritis/nephritis/arthritis in the recipient mice. Collectively, ECP or BPI overexpression in T-cell-derived exosomes or T cells are novel biomarkers and pathogenic factors for human SLE nephritis, hepatitis, and arthritis.