Khanolkar A, Yagita H, Cannon M J
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Virology. 2001 Aug 15;287(1):79-88. doi: 10.1006/viro.2001.1020.
In this report, we show that Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines (LCL) express Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 and that LCL are lysed following engagement of these receptors by agonist Fas and TRAIL receptor-specific monoclonal antibodies (MAb). We also show that EBV-specific CD4+ T cells mediate bystander lysis of susceptible targets through both the Fas/Fas ligand (FasL) and the TRAIL pathways, but find that the dominant mechanism of lysis following cognate, HLA class II-restricted recognition of LCL is the perforin/granzyme pathway. Killing of LCL by EBV-specific CD4+ T cells was strongly inhibited by concanamycin A, an agent that elevates granule pH, resulting in accelerated destabilization and degradation of perforin. In contrast, blocking anti-FasL MAb showed only limited inhibition of LCL killing. Blocking anti-TRAIL MAb had no effect on lysis of LCL by EBV-specific CD4+ T cells. We further show that culture of EBV-specific CD4+ T cells in the presence of interleukin 4 markedly abrogates effector cytotoxic function against LCL through direct depletion of intracellular perforin, with no evidence of a Th1 to Th2 shift in patterns of cytokine expression.
在本报告中，我们表明，爱泼斯坦-巴尔病毒（EBV）感染的淋巴母细胞系（LCL）表达Fas和肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体2，并且在用激动剂Fas和TRAIL受体特异性单克隆抗体（MAb）使这些受体结合后，LCL会被裂解。我们还表明，EBV特异性CD4 + T细胞通过Fas/Fas配体（FasL）和TRAIL途径介导对易感靶标的旁观者裂解，但发现同源的、HLA II类限制性识别LCL后，裂解的主要机制是穿孔素/颗粒酶途径。EBV特异性CD4 + T细胞对LCL的杀伤作用被 concanamycin A强烈抑制，concanamycin A是一种可提高颗粒pH值的药物，会导致穿孔素加速去稳定化和降解。相比之下，阻断抗FasL MAb仅对LCL杀伤有有限的抑制作用。阻断抗TRAIL MAb对EBV特异性CD4 + T细胞裂解LCL没有影响。我们进一步表明，在白细胞介素4存在的情况下培养EBV特异性CD4 + T细胞，通过直接消耗细胞内穿孔素，显著消除了针对LCL的效应细胞毒性功能，且没有证据表明细胞因子表达模式从Th1向Th2转变。
