Epigenetic Control of Killer Immunoglobulin-like Receptor (KIR) Expression in T cells (35.40)

Abstract

Abstract Killer immunoglobulin-like receptors (KIR), usually restricted to NK cells, are expressed on T-cells with increasing age and contribute to age-related diseases. We examined the epigenetic changes associated with KIR expression. In T cells with absent KIR2DL4 transcripts such as the Jurkat cell line or CD4+CD28+ T cells, CpG sites of the proximal KIR2DL4 promoter were hypermethylated. DNMT inhibition in such cells induced low but appreciable KIR2DL4 transcription. DNMT inhibition was strikingly more effective in T cells that had some constitutive KIR2DL4 transcription, such as CD4 and CD8 T cells from elderly adults or the CD4+CD28−T cell line HUT78. Such cells had evidence of partial promoter demethylation; however, although the proximal nucleosome was partially relaxed, the only histone modification was an increase in dimethylated H3-Lys 4. In contrast, NK cells had a fully demethylated KIR2DL4 promoter and the full spectrum of histone modifications indicative of active transcription with H3 and H4 acetylation, di- and trimethylated H3-Lys 4, and reduced dimethylated H3-Lys 9. These results suggest that early steps of promoter activation in T cells include selective increase in H3-Lys 4 dimethylation and limited DNA demethylation. This partially accessible promoter is sensitive to DNMT inhibition, which is sufficient to induce full transcription without further histone acetylation and methylation. Supported by NIH grant AG 15043