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

Abstract

ObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from patients with lupus and controls and investigated the functional relevance of some of these changes in lupus.MethodsGenome-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. Inhibiting STAT1 and CIITA was performed using fludarabine and CIITA siRNA, respectively.ResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared with 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. CIITA knockdown and STAT1 inhibition experiments revealed that HLA-DRB1 expression in lupus CD8+ T cells is dependent on CIITA and STAT1 signalling. Coincubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69 and cytokine production, in patients with lupus but not in healthy controls. This can be blocked by neutralising antibodies targeting HLA-DR.ConclusionsLupus 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 patients with lupus. A possible pathogenic role for CD8+ T cells in lupus that is dependent on a high type-I interferon environment and epigenetic priming warrants further characterisation.

Genome-Wide DNA Methylation in Policemen Working in Cities Differing by Major Sources of Air Pollution

“…Comparing Ostrava and Prague, the most hypomethylated DML was found to be CpG locus cg10123377. This CpG locus was also found in the study of patients with systematic lupus erythematosus in CD8T+ cells [38]. Two of the hypermethylated loci (cg11478607 and cg26946806) located in Island and S Shore, respectively, are annotated to the GSTT1-encoding xenobiotic metabolizing enzyme, which plays an important role in human carcinogenesis [39] and impacts the markers of genotoxicity [40].…”

Current Understanding of an Emerging Role of HLA-DRB1 Gene in Rheumatoid Arthritis–From Research to Clinical Practice

“…Consistently, the rs9267649 protective variant was associated with increased DNA methylation and lower HLA-DRB1 expression in multiple sclerosis [119]. Furthermore, hypomethylation of HLA-DRB1 loci also induces HLA-DRB1 expression in systemic lupus erythematosus CD8+ T cells [120]. The HLA-DRB1 methylation status is likely to be relevant to RA, also.…”

Genome-Wide DNA Methylation Profile in Whole Blood of Patients With Chronic Spontaneous Urticaria

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