Ashton-Rickardt Philip G
The University of Chicago, Department of Pathology and Ben May Institute for Cancer Research, 924 E. 57th Street, Chicago, IL 60637, USA.
Crit Rev Immunol. 2005;25(3):161-82. doi: 10.1615/critrevimmunol.v25.i3.10.
The exocytosis of death-inducing granzymes stored in the granules of cytotoxic lymphocytes allows the immune system to rapidly eliminate intracellular pathogens and transformed cells. The membrane-disrupting protein perforin allows the entry of granzymes into a cell, where they induce apoptosis by cleaving target substrates in the cytoplasm and nucleus. Granzymes kill cells in a variety of ways. Recent work has demonstrated that granzymes induce mitochondrial dysfunction through caspase and caspase-independent pathways and destroy DNA and the integrity of the nucleus. Cytotoxic lymphocytes are susceptible to self-inflicted damage. Mice and humans defective in perforin and granzymes point to a role for self-inflicted damage in downregulating lymphocyte responses. Given the propensity for the granule pathway to inflict cellular damage, cytotoxic lymphocytes have developed a variety of mechanisms to protect themselves. In this regard, endogenous serine protease inhibitors have been suggested to protect cytotoxic lymphocytes from granzyme B. It would appear that certain viruses and possibly even tumor cells also use the same mechanism to escape destruction from the exocytosis pathway of programmed cell death.
储存在细胞毒性淋巴细胞颗粒中的促死亡颗粒酶的胞吐作用，使免疫系统能够迅速清除细胞内病原体和转化细胞。膜破坏蛋白穿孔素可使颗粒酶进入细胞，在细胞内，颗粒酶通过切割细胞质和细胞核中的靶底物来诱导细胞凋亡。颗粒酶以多种方式杀死细胞。最近的研究表明，颗粒酶通过半胱天冬酶和非半胱天冬酶依赖性途径诱导线粒体功能障碍，并破坏DNA和细胞核的完整性。细胞毒性淋巴细胞易受自身造成的损伤。穿孔素和颗粒酶缺陷的小鼠和人类表明，自身造成的损伤在下调淋巴细胞反应中起作用。鉴于颗粒途径易于造成细胞损伤，细胞毒性淋巴细胞已发展出多种保护自身的机制。在这方面，内源性丝氨酸蛋白酶抑制剂被认为可以保护细胞毒性淋巴细胞免受颗粒酶B的侵害。似乎某些病毒甚至肿瘤细胞也利用相同的机制逃避程序性细胞死亡胞吐途径的破坏。
