NK cells are primarily responsible for detecting malignant or pathogen-infected cells, and their function is influenced both by stress-associated activating signals and opposing inhibitory signals from receptors that recognize self MHC. The receptors that produce this inhibitory signal shift from the NKG2A:HLA-E system to that of KIR:HLA as the NK cells mature. This maturation is associated with an increase in lytic activity, as well as an increase in HLA-C protein levels controlled by the NK-specific HLA-C promoter, NK-Pro. We propose that modulation of the translatability of HLA-C transcripts in NK cells constitutes an evolutionary mechanism to control cis inhibitory signaling by HLA-C, which fine tunes NK cell activity. Furthermore, the high degree of variability in KIR receptor affinity for HLA alleles, as well as the variable expression levels of both KIR and HLA, suggest an evolutionary requirement for the tuning of NK lytic activity. Various data have demonstrated that mature NK cells may gain or lose lytic activity when placed in different environments. This indicates that NK cell activity may be more a function of constant tuning by inhibitory signals, rather than a static, irreversible "license to kill" granted to mature NK cells. Inhibitory signaling controls the filling of the cytolytic granule reservoir, which becomes depleted if there are insufficient inhibitory signals, leading to a hyporesponsive NK cell. We propose a novel model for the tuning of human NK cell activity via cis interactions in the context of recent findings on the mechanism of NK education.

中文翻译：

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通过内源性 HLA-C 表达调节人类 NK 细胞。

NK 细胞主要负责检测恶性或病原体感染的细胞，其功能受到应激相关激活信号和识别自身 MHC 受体的反向抑制信号的影响。随着 NK 细胞的成熟，产生这种抑制信号的受体从 NKG2A:HLA-E 系统转移到 KIR:HLA 系统。这种成熟与裂解活性的增加以及由 NK 特异性 HLA-C 启动子 NK-Pro 控制的 HLA-C 蛋白水平的增加有关。我们提出，调节 NK 细胞中 HLA-C 转录本的可翻译性构成了控制 HLA-C 顺式抑制信号传导的进化机制，从而微调 NK 细胞活性。此外，KIR 受体对 HLA 等位基因的亲和力的高度变异性，以及 KIR 和 HLA 的表达水平的可变性，表明调节 NK 裂解活性的进化要求。各种数据表明，成熟的 NK 细胞在置于不同环境中时可能会获得或失去裂解活性。这表明 NK 细胞活性可能更多地是抑制信号不断调节的函数，而不是授予成熟 NK 细胞的静态、不可逆的“杀伤许可”。抑制信号控制细胞溶解颗粒储库的填充，如果抑制信号不足，细胞溶解颗粒储库就会耗尽，导致 NK 细胞反应低下。我们根据 NK 教育机制的最新发现，提出了一种通过顺式相互作用调节人类 NK 细胞活性的新模型。