Ligation of CD8α on human natural killer cells prevents activation-induced apoptosis and enhances cytolytic activity
Ligation of CD8α on human natural killer cells prevents activation-induced apoptosis and enhances cytolytic activity
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DOI：
10.1111/j.1365-2567.2005.02235.x
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发表时间：
2005-11-01
期刊：
影响因子：
6.4
通讯作者：
Lowdell, MW
中科院分区：
文献类型：
--
作者：
Addison, EG;North, J;Lowdell, MW
先前已表明，以同源二聚体α/α形式表达CD8的人类自然杀伤（NK）细胞亚群比其CD8阴性的对应细胞更具细胞毒性，但这种差异细胞溶解活性背后的机制仍不清楚。CD8阴性NK细胞对靶细胞的裂解与效应细胞的高水平凋亡相关，这与相同靶细胞裂解后在CD8α阳性细胞中发现的显著较低水平形成对比。我们报道，NK细胞上CD8α链的交联通过引发细胞外Ca(2+)离子内流，诱导细胞内Ca(2+)快速升高以及细胞表面CD69表达增加。我们证明，细胞溶解酶的分泌引发NK细胞凋亡，而NK细胞表面CD8结合后外源性钙的内流保护CD8α阳性NK细胞免受凋亡。这种结合是通过与细胞结合物中的其他NK细胞相互作用发生的，并且当靶细胞缺乏主要组织相容性复合体（MHC）I类表达时也可能发生。用抗MHC I类抗体预孵育NK细胞可阻断对凋亡的保护作用。因此，与CD8阴性亚群相反，CD8α阳性NK细胞能够连续裂解多个靶细胞。
It has been previously shown that the subset of human natural killer (NK) cells which express CD8 in a homodimeric alpha/alpha form are more cytotoxic than their CD8(-) counterparts but the mechanisms behind this differential cytolytic activity remained unknown. Target cell lysis by CD8(-) NK cells is associated with high levels of effector cell apoptosis, which is in contrast to the significantly lower levels found in the CD8 alpha(+) cells after lysis of the same targets. We report that cross-linking of the CD8 alpha chains on NK cells induces rapid rises in intracellular Ca(2+) and increased expression of CD69 at the cell surface by initiating the influx of extracellular Ca(2+) ions. We demonstrate that secretion of cytolytic enzymes initiates NK-cell apoptosis from which CD8 alpha(+) NK cells are protected by an influx of exogenous calcium following ligation of CD8 on the NK-cell surface. This ligation is through interaction with fellow NK cells in the cell conjugate and can occur when the target cells lack major histocompatibility complex (MHC) Class I expression. Protection from apoptosis is blocked by preincubation of the NK cells with anti-MHC Class I antibody. Thus, in contrast to the CD8(-) subset, CD8 alpha(+) NK cells are capable of sequential lysis of multiple target cells.