Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection
Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection
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DOI：
10.1073/pnas.1501662112
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发表时间：
2015-07-21
影响因子：
11.1
通讯作者：
Zeng, Gucheng
中科院分区：
文献类型：
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作者：
Wang, Yang;Zhong, Huiling;Zeng, Gucheng
结核(TB)感染过程中T细胞抑制分子调节T细胞免疫反应的分子机制尚不清楚。在这里，我们发现活动性的人类结核病感染上调了CD8(+)T细胞中的CD244和CD244信号相关分子，并且CD244信号的阻断增强了干扰素-γ和肿瘤坏死因子-α的产生。CD244在TB中的表达/信号与CD244(+)CD8(+)T细胞亚群中长非编码RNA(LncRNA)-BC050410[命名为lncRNA-as-GSTT1(1-72)或lncRNA-CD244]的高水平相关。CD244信号通过维持lncRNA-CD244位点的染色质状态来驱动lncRNA-CD244的表达。LncRNA-CD244通过将Zust同源基因的多梳蛋白增强子2(EZH2)募集为INFg/TNFa启动子，介导INFg/TNFa基因座的H3K27三甲基化进入抑制性染色质状态，并抑制CD8(+)T细胞中干扰素-γ/肿瘤坏死因子-α的表达。这种抑制可以通过敲除lncRNA-CD244而逆转。有趣的是，过继将lncRNA-CD244抑制的CD8(+)T细胞转移到结核分枝杆菌(MTB)感染的小鼠，与表达lncRNA-CD244的对照组相比，减少了MTB感染和结核病病理。因此，这项工作揭示了以前未知的机制，其中T细胞抑制信号和lncRNAs调节T细胞反应和宿主对结核病感染的防御。
Molecular mechanisms for T-cell immune responses modulated by T cell-inhibitory molecules during tuberculosis (TB) infection remain unclear. Here, we show that active human TB infection up-regulates CD244 and CD244 signaling-associated molecules in CD8(+) T cells and that blockade of CD244 signaling enhances production of IFN-gamma and TNF-alpha. CD244 expression/signaling in TB correlates with high levels of a long noncoding RNA (lncRNA)-BC050410 [named as lncRNA-AS-GSTT1(1-72) or lncRNA-CD244] in the CD244(+)CD8(+) T-cell subpopulation. CD244 signaling drives lncRNA-CD244 expression via sustaining a permissive chromatin state in the lncRNA-CD244 locus. By recruiting polycomb protein enhancer of zeste homolog 2 (EZH2) to infg/tnfa promoters, lncRNA-CD244 mediates H3K27 trimethylation at infg/tnfa loci toward repressive chromatin states and inhibits IFN-gamma/TNF-alpha expression in CD8(+) T cells. Such inhibition can be reversed by knock down of lncRNA-CD244. Interestingly, adoptive transfer of lncRNA-CD244-depressed CD8(+) T cells to Mycobacterium tuberculosis (MTB)-infected mice reduced MTB infection and TB pathology compared with lncRNA-CD244-expressed controls. Thus, this work uncovers previously unidentified mechanisms in which T cell-inhibitory signaling and lncRNAs regulate T-cell responses and host defense against TB infection.