Multiplicity and plasticity of natural killer cell signaling pathways
Multiplicity and plasticity of natural killer cell signaling pathways
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DOI：
10.1182/blood-2005-08-3504
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发表时间：
2006-03-15
期刊：
影响因子：
20.3
通讯作者：
Tomasello, E
中科院分区：
文献类型：
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作者：
Chiesa, S;Mingueneau, M;Tomasello, E
自然杀伤(NK)细胞表达一系列与DAP12(Karap)、CD3 Zeta和/或FCR Gamma ITAM(基于免疫受体酪氨酸的激活基序)相关的激活受体。在T细胞和肥大细胞中，ITAM依赖的信号被关键的支架元件整合，如LAT(激活T细胞的连接物)和NTAL(非T细胞激活连接物)。利用缺乏携带ITAM分子LAT或NTAL的小鼠，我们发现NK细胞的细胞毒性和干扰素-γ的分泌是由ITAM依赖和非依赖以及LAT/NTAL依赖和非依赖途径启动的。这些不同的信号通路的作用取决于靶细胞以及NK细胞的激活状态。启动NK细胞效应器功能的途径的多样性和可塑性与T细胞和B细胞的情况形成对比，并解释了墨水细胞效应器功能对各种药物抑制剂和信号分子中的基因突变的弹性。
Natural killer (NK) cells express an array of activating receptors that associate with DAP12 (KARAP), CD3 zeta, and/or FcR gamma ITAM (immunoreceptor tyrosine-based activation motif)-bearing signaling subunits. In T and mast cells, ITAM-dependent signals are integrated by critical scaffolding elements such as LAT (linker for activation of T cells) and NTAL (non-T-cell activation linker). Using mice that are deficient for ITAM-bearing molecules, LAT or NTAL, we show that NK cell cytotoxicity and interferon-gamma secretion are initiated by ITAM-dependent and -independent as well as LAT/NTAL-dependent and -independent pathways. The role of these various signaling circuits depends on the target cell as well as on the activation status of the NK cell. The multiplicity and the plasticity of the pathways that initiate NK cell effector functions contrast with the situation in T cells and B cells and provide an explanation for the resiliency of INK cell effector functions to various pharmacologic inhibitors and genetic mutations in signaling molecules.