Zhang Manling, Park Sun-Mi, Wang Yue, Shah Ramila, Liu Ni, Murmann Andrea E, Wang Chyung-Ru, Peter Marcus E, Ashton-Rickardt Philip G
Department of Pathology, The University of Chicago, 924 East 57th Street, Illinois 60637, USA.
Immunity. 2006 Apr;24(4):451-61. doi: 10.1016/j.immuni.2006.02.002.
How cytotoxic T lymphocytes (CTLs) kill intracellular pathogens without killing themselves has been a recurring question ever since their discovery. By using mice deficient in Serine Protease Inhibitor 6 (Spi6), we show that by inhibiting granzyme B (GrB), Spi6 protects CTLs from self-inflicted injury. Infection with either Lymphocytic Choriomeningitis virus (LCMV) or Listeria monocytogenes (LM) revealed increased apoptosis and diminished survival of Spi6 knockout (KO) CTLs, which was cell autonomous and could be corrected by GrB deficiency. Spi6 KO mice in turn were impaired in their ability to clear LCMV infection. Spi6 KO CTLs revealed a breakdown in the integrity of cytotoxic granules, increased cytoplasmic GrB, and ensuing apoptosis. We conclude that Spi6 protects CTLs from suicide caused by GrB-mediated breakdown of cytotoxic granules.
自从细胞毒性T淋巴细胞（CTLs）被发现以来，它们如何在不自我杀伤的情况下杀死细胞内病原体一直是一个反复出现的问题。通过使用丝氨酸蛋白酶抑制剂6（Spi6）缺陷的小鼠，我们发现Spi6通过抑制颗粒酶B（GrB）来保护CTLs免受自身造成的损伤。感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）或单核细胞增生李斯特菌（LM）后，Spi6基因敲除（KO）的CTLs凋亡增加且存活率降低，这是细胞自主性的，并且可以通过GrB缺陷得到纠正。反过来，Spi6 KO小鼠清除LCMV感染的能力受损。Spi6 KO的CTLs表现出细胞毒性颗粒完整性的破坏、细胞质GrB增加以及随之而来的细胞凋亡。我们得出结论，Spi6保护CTLs免受由GrB介导的细胞毒性颗粒破坏所导致的自杀。
