PT - JOURNAL ARTICLE AU - Shaylynn Miller AU - Patrick Coit AU - Elizabeth Gensterblum-Miller AU - Paul Renauer AU - Nathan C Kilian AU - Mark Schonfeld AU - Pei-Suen Tsou AU - Amr H Sawalha TI - Hypomethylation of <em>STAT1</em> and <em>HLA-DRB1</em> is associated with type-I interferon-dependent <em>HLA-DRB1</em> expression in lupus CD8+ T cells AID - 10.1101/398081 DP - 2018 Jan 01 TA - bioRxiv PG - 398081 4099 - http://biorxiv.org/content/early/2018/08/22/398081.short 4100 - http://biorxiv.org/content/early/2018/08/22/398081.full AB - Objective We examined genome-wide DNA methylation changes in CD8+ T cells from lupus patients and controls, and investigated the functional relevance of some of these changes in lupus.Methods Genome-wide DNA methylation of lupus and age, sex, and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR.Results Lupus CD8+ T cells had 188 hypomethylated CpG sites compared to healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. Co-incubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69, in lupus patients but not in healthy controls. This can be blocked by neutralizing antibodies targeting HLA-DR.Conclusions Lupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in lupus patients. A possible pathogenic role for CD8+ T cells in lupus that is dependent upon a high type-I interferon environment and epigenetic priming warrants further characterization.