Li Guangjin, Yu Mingcan, Weyand Cornelia M, Goronzy Jörg J
Kathleen B. and Mason I. Lowance Center for Human Immunology and Rheumatology, Emory University, Atlanta, GA 30322, USA.
Blood. 2009 Oct 15;114(16):3422-30. doi: 10.1182/blood-2009-01-200170. Epub 2009 Jul 23.
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.
随着年龄的增长，T细胞获得杀伤免疫球蛋白样受体（KIR）的表达，这些受体传递负信号并抑制免疫反应。CpG DNA去甲基化可诱导CD4和CD8 T细胞中KIR的表达，提示存在表观遗传调控。为了确定CD8 T细胞中与年龄相关的KIR优先表达的潜在机制，我们检测了KIR2DL3启动子的甲基化模式。随着年龄的增长，即使在不表达KIR2DL3编码的CD158b蛋白的细胞中，CD8 T细胞也会出现斑驳且随机的启动子去甲基化；最小KIR2DL3启动子的完全去甲基化是表达CD158b细胞的特征。相比之下，CD4 T细胞中的启动子无论年龄如何均完全甲基化。CD8 T细胞的这种选择性与较低的DNMT1募集到KIR2DL3启动子相关，且随着年龄的增长这种募集进一步减少。相反，已知参与DNMT1募集的多梳蛋白EZH2的结合没有差异。我们的数据表明，随着年龄的增长，CD8 T细胞中KIR启动子上的DNMT1不断被取代，这可能是由于活跃的组蛋白特征所致。随之而来的部分去甲基化降低了转录激活的阈值，使CD8 T细胞更容易表达KIR，从而导致老年人的免疫缺陷。
