Thoma-Uszynski S, Stenger S, Modlin R L
Division of Dermatology, Department of Microbiology and Immunology and Molecular Biology Institute, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095, USA.
J Immunol. 2000 Nov 15;165(10):5773-9. doi: 10.4049/jimmunol.165.10.5773.
Two subsets of human CTL have been defined based upon phenotype and function: CD4(-) CD8(-) double-negative (DN) CTL lyse susceptible targets via Fas-Fas ligand interaction and CD8(+) CTL via the granule exocytosis pathway. CD8(+) CTL, but not DN CTL, can mediate an antimicrobial activity against Mycobacterium tuberculosis-infected target cells that is dependent on cytotoxic granules that contain granulysin. We investigated the role of nuclear apoptosis for the antimicrobial effector function of CD1-restricted CTL using the caspase inhibitor N:-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. We found that DN CTL-induced target cell lysis was completely dependent on caspase activation, whereas the cytolytic activity of CD8(+) CTL was caspase independent. However, both DN and CD8(+) CTL-induced nuclear apoptosis required caspase activation. More important, the antimicrobial effector function of CD8(+) CTL was not diminished by inhibition of caspase activity. These data indicate that target cell nuclear apoptosis is not a requirement for CTL-mediated killing of intracellular M. tuberculosis.
基于表型和功能，已定义了人类细胞毒性T淋巴细胞（CTL）的两个亚群：CD4(-) CD8(-)双阴性（DN）CTL通过Fas-Fas配体相互作用裂解敏感靶细胞，而CD8(+) CTL则通过颗粒胞吐途径发挥作用。CD8(+) CTL而非DN CTL可介导针对结核分枝杆菌感染靶细胞的抗菌活性，该活性依赖于含有颗粒溶素的细胞毒性颗粒。我们使用半胱天冬酶抑制剂N-苄氧羰基-Val-Ala-Asp-氟甲基酮研究了核凋亡在CD1限制性CTL抗菌效应功能中的作用。我们发现，DN CTL诱导的靶细胞裂解完全依赖于半胱天冬酶激活，而CD8(+) CTL的细胞溶解活性则不依赖于半胱天冬酶。然而，DN和CD8(+) CTL诱导的核凋亡均需要半胱天冬酶激活。更重要的是，抑制半胱天冬酶活性并不会削弱CD8(+) CTL的抗菌效应功能。这些数据表明，靶细胞核凋亡并非CTL介导杀灭细胞内结核分枝杆菌的必要条件。
