OBJECTIVES: T cells play critical roles in the pathogenesis of systemic lupus erythematosus (SLE). Serum-derived exosomes are increased in SLE patients and are correlated with disease severity. The proteins in the T-cell-derived exosomes from SLE patients could play important roles in SLE pathogenesis. METHODS: We characterized proteins of SLE T cell-derived exosomes by exosome MACSPlex analysis and proteomics using T-cell supernatants from SLE patients and healthy controls. To study the potential pathogenic functions of the identified exosomal protein, we generated and characterized T-cell-specific transgenic mice that overexpressed the identified protein in T cells. RESULTS: We identified eosinophil cationic protein (ECP, also named human RNase 3) that was overexpressed in SLE T cell-derived exosomes. T-cell-specific ECP transgenic mice displayed early induction of serum IFN-γ levels and multi-tissue inflammation. The aged T-cell-specific ECP transgenic mice also displayed an increase of follicular helper T cells, plasma B cell, and autoantibodies. Single-cell RNA sequencing (scRNA-seq) also showed the induction of IFN-γ mRNA and inflammatory pathways in ECP transgenic T cells. Remarkably, adoptively transferred ECP-containing exosomes stimulated serum levels of IFN-γ and autoantibodies in the recipient mice. The transferred exosomes infiltrated into multiple tissues of the recipient mice, resulting in hepatitis, nephritis, and arthritis. CONCLUSIONS: ECP overexpression in T cells or T-cell-derived exosomes may be a biomarker and pathogenic factor for human SLE nephritis, hepatitis, and arthritis.
Date:
2022-01
Relation:
Arthritis and Rheumatology. 2022 Jan;74(1):92-104.
