Hypomethylation of STAT1 and HLA-DRB1 in CD8+ T cells is associated with type-I interferon dependent activation of CD4+ T cells in systemic lupus erythematosus

Abstract

Abstract Background Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by autoantibody and type I interferon (IFN) production. The goal of this study was to explore possible pathogenic roles of CD8+ T cells in lupus through characterizing DNA methylation changes. Methods Genome-wide DNA methylation of SLE and matched healthy control CD8+ T cells was measured using Infinium Human Methylation 450k arrays. Cell surface expression of HLA-DRB1 on CD8+ T cells with and without IFNα was measured by flow cytometry. Co-incubation of IFNα-treated CD8+ T cells with autologous naïve CD4+ T cells was performed. Results SLE CD8+ T cells had 188 hypomethylated CpG sites compared to healthy controls. Among the most demethylated were sites associated with HLA-DRB1 (Δβ = −0.33) and STAT1 (Δβ = −0.15). The proportion of CD8+ T cells expressing HLA-DRB1 was significantly higher in SLE compared to controls. Treatment with IFNα upregulated cell surface expression of HLA-DRB1 on CD8+ T cells of SLE patients but not healthy controls, as measured by median fluorescence intensity. Co-incubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to increased expression of the stimulation marker CD69 on CD4+ T cells in SLE patients, but not in healthy controls. There was a significant increase in STAT1 mRNA levels in both SLE patients and controls with IFNα treatment. Conclusion HLA-DRB1 and STAT1 loci are hypomethylated and epigenetically poised for overexpression in SLE CD8+ T cells in the presence of type-I interferon. IFNα-treated lupus CD8+ T cells stimulate autologous CD4+ T cells in vitro. These data suggest a possible pathogenic role for CD8+ T cells that is dependent upon a high type-I interferon environment in SLE patients.