Aberrant T cell KIR demethylation in the pathogenesis of lupus

Abstract

Human lupus is an epigenetic disease. Some lupus‐inducing drugs are DNA methylation inhibitors, and T cell DNA demethylation causes lupus in mice through aberrant expression of genes causing macrophage (Mø) apoptosis and B cell overstimulation. Identical T cell DNA demethylation contributes to human lupus by overexpression of the same molecules. Molecules expressed on demethylated but not normal T cells, and which inactivate the pathologic T cells, would be ideal targets for treating lupus. We treated human T cells with a DNA methylation inhibitor, identified overexpressed genes with microarrays, and selected the KIR gene family from the >300 genes induced. KIR genes are normally expressed on NK but not T cells, and deliver inhibitory or stimulatory signals depending on the gene. KIR promoter demethylation was confirmed by bisulfite sequencing and function by cassette methylation. Crosslinking the inhibitory KIR prevented Mø killing by demethylated cells. T cells from lupus patients lupus aberrantly expressed the KIR family, and crosslinking inhibitory KIR blocked autologous Mø killing. Anti‐KIR may be an effective treatment for human lupus. Supported by PHS grants AR42525, AG25877 and ES015214.