Epigenetic regulation of killer immunoglobulin–like receptor expression in T cells
Year: 2009
Type: article
Abstract: With increasing age, T cells gain expression of killer immunoglobulin-like receptors (KIRs) that transmit negative signals and dampen the immune response. KIR expression is induced in CD4 and CD8 T cells by CpG DNA demethylation suggesting epigenetic control. To define the mechanisms that underlie the age-associated preferential KIR expression in CD8 T cells, we examined KIR2DL3 promoter methylation patterns. With age, CD8 T cells developed a patchy and stochastic promoter demethylation even in cells that did not express the KIR2DL3-encoded CD158b protein; complete demethylation of the minimal KIR2DL3 promoter was characteristic for CD158b-expressing cells. In contrast, the promoter in CD4 T cells was fully methylated irrespective of age. The selectivity for CD8 T cells correlated with lower DNMT1 recruitment to the KIR2DL3 promoter which further diminished with age. In contrast, binding of the polycomb protein EZH2 known to be involved in DNMT1 recruitment was not different. Our data suggest that CD8 T cells endure increasing displacement of DNMT1 from the KIR promoter with age, possibly because of an active histone signature. The ensuing partial demethylation lowers the threshold for transcriptional activation and renders CD8 T cells more susceptible to express KIR, thereby contributing to the immune defect in the elderly.
Source: Blood
Authors: Guangjin Li, Mingcan Yu, Cornelia M. Weyand, Jörg J. Goronzy
Institution: Emory University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: National Institutes of Health, School of Medicine, Emory University, National Institute on Aging, National Heart, Lung, and Blood Institute, National Eye Institute, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Awards: CD8 T Cells in Rheumatoid Arthritis, G1911962955, G2260927788, G2540523102, G353744, G366100091, Oligoclonal T Cell Expansion and Rheumatoid Arthritis, G429955531, G64106078, G661928818, Ocular Disease in Giant Cell Arteritis, G8039560308, The NOTCH Signaling Pathway in Large Vessel Vasculitis, Vaccine and Infection Induced Immunity in the Young and Aged, G953332266, G971417677
OpenAlex ID: W1985294707