Zamai L, Ahmad M, Bennett I M, Azzoni L, Alnemri E S, Perussia B
Jefferson Medical College, Department of Microbiology and Immunology, Kimmel Cancer Institute, Philadelphia, Pennsylvania 19107, USA.
J Exp Med. 1998 Dec 21;188(12):2375-80. doi: 10.1084/jem.188.12.2375.
Mature natural killer (NK) cells use Ca2+-dependent granule exocytosis and release of cytotoxic proteins, Fas ligand (FasL), and membrane-bound or secreted cytokines (tumor necrosis factor [TNF]-alpha) to induce target cell death. Fas belongs to the TNF receptor family of molecules, containing a conserved intracytoplasmic "death domain" that indirectly activates the caspase enzymatic cascade and ultimately apoptotic mechanisms in numerous cell types. Two additional members of this family, DR4 and DR5, transduce apoptotic signals upon binding soluble TNF-related apoptosis-inducing ligand (TRAIL) that, like FasL, belongs to the growing TNF family of molecules. Here, we report that TRAIL produced or expressed by different populations of primary human NK cells is functional, and represents a marker of differentiation or activation of these, and possibly other, cytotoxic leukocytes. During differentiation NK cells, sequentially and differentially, use distinct members of the TNF family or granule exocytosis to mediate target cell death. Phenotypically immature CD161(+)/CD56(-) NK cells mediate TRAIL-dependent but not FasL- or granule release-dependent cytotoxicity, whereas mature CD56(+) NK cells mediate the latter two.
成熟的自然杀伤（NK）细胞利用钙离子依赖性颗粒胞吐作用以及释放细胞毒性蛋白、Fas配体（FasL）和膜结合或分泌的细胞因子（肿瘤坏死因子[TNF]-α）来诱导靶细胞死亡。Fas属于TNF受体家族分子，含有保守的胞质内“死亡结构域”，可间接激活半胱天冬酶酶促级联反应，并最终在多种细胞类型中激活凋亡机制。该家族的另外两个成员DR4和DR5，在结合可溶性TNF相关凋亡诱导配体（TRAIL）时转导凋亡信号，TRAIL与FasL一样，属于不断增加的TNF家族分子。在此，我们报告，由不同群体的原代人NK细胞产生或表达的TRAIL具有功能，并且代表这些以及可能其他细胞毒性白细胞的分化或激活标志物。在分化过程中，NK细胞依次且有差异地使用TNF家族的不同成员或颗粒胞吐作用来介导靶细胞死亡。表型不成熟的CD161(+)/CD56(-) NK细胞介导TRAIL依赖性而非FasL或颗粒释放依赖性细胞毒性，而成熟的CD56(+) NK细胞介导后两者。
