Smith Corey, Wakisaka Naohiro, Crough Tania, Peet Jesse, Yoshizaki Tomokazu, Beagley Leone, Khanna Rajiv
Australian Centre for Vaccine Development and Tumour Immunology Laboratory, Division of Immunology, Queensland Institute of Medical Research, Brisbane, Australia.
Blood. 2009 Jun 11;113(24):6148-52. doi: 10.1182/blood-2009-02-203687. Epub 2009 Apr 16.
Activation of the nuclear factor-kappaB pathway by Epstein-Barr virus-encoded latent membrane protein-1 (LMP-1) leads to an up-regulation of the major histocompatibility complex class I antigen-processing pathway. Paradoxically, LMP-1 itself induces a subdominant CD8+ T-cell response and appears to have evolved to avoid immune recognition. Here we show that, although expression of LMP-1 in human cells dramatically enhanced the trans-presentation of CD8+ T-cell epitopes, cis-presentation of LMP-1-derived epitopes was severely impaired. Testing of a series of LMP-1 mutants revealed that deletion of the first transmembrane domain of LMP-1, which prevented self-aggregation, significantly enhanced cis-presentation of T-cell epitopes from this protein, whereas it lost its ability to up-regulate trans-presentation. Interestingly, we also found that cis-presentation of LMP-1 epitopes was rescued by blocking the proteasome function. Taken together, these results delineate a novel mechanism of immune evasion, which renders a virally encoded oncogene inaccessible to the conventional major histocompatibility complex class I pathway limiting its cis-presentation to effector cells.
爱泼斯坦-巴尔病毒编码的潜伏膜蛋白1（LMP-1）激活核因子-κB途径会导致主要组织相容性复合体I类抗原加工途径上调。矛盾的是，LMP-1本身诱导的CD8+ T细胞反应较弱，似乎已经进化到可避免免疫识别。我们在此表明，尽管LMP-1在人细胞中的表达显著增强了CD8+ T细胞表位的反式呈递，但LMP-1衍生表位的顺式呈递却严重受损。对一系列LMP-1突变体的测试表明，缺失LMP-1的第一个跨膜结构域可防止其自身聚集，这显著增强了该蛋白T细胞表位的顺式呈递，但其上调反式呈递的能力丧失。有趣的是，我们还发现通过阻断蛋白酶体功能可挽救LMP-1表位的顺式呈递。综上所述，这些结果描绘了一种新的免疫逃逸机制，该机制使病毒编码的癌基因无法通过传统的主要组织相容性复合体I类途径呈递给效应细胞，从而限制了其顺式呈递。
