Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia School of Medicine, The University of Queensland, Brisbane, Australia.
Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
J Virol. 2015 Jan;89(1):703-12. doi: 10.1128/JVI.02642-14. Epub 2014 Oct 29.
Polymorphism in the human leukocyte antigen (HLA) loci ensures that the CD8(+) T cell response to viruses is directed against a diverse range of antigenic epitopes, thereby minimizing the impact of virus escape mutation across the population. The BZLF1 antigen of Epstein-Barr virus is an immunodominant target for CD8(+) T cells, but the response has been characterized only in the context of a limited number of HLA molecules due to incomplete epitope mapping. We have now greatly expanded the number of defined CD8(+) T cell epitopes from BZLF1, allowing the response to be evaluated in a much larger proportion of the population. Some regions of the antigen fail to be recognized by CD8(+) T cells, while others include clusters of overlapping epitopes presented by different HLA molecules. These highly immunogenic regions of BZLF1 include polymorphic sequences, such that up to four overlapping epitopes are impacted by a single amino acid variation common in different regions of the world. This focusing of the immune response to limited regions of the viral protein could be due to sequence similarity to human proteins creating "immune blind spots" through self-tolerance. This study significantly enhances the understanding of the immune response to BZLF1, and the precisely mapped T cell epitopes may be directly exploited in vaccine development and adoptive immunotherapy.
Epstein-Barr virus (EBV) is an important human pathogen, associated with several malignancies, including nasopharyngeal carcinoma and Hodgkin lymphoma. T lymphocytes are critical for virus control, and clinical trials aimed at manipulating this arm of the immune system have demonstrated efficacy in treating these EBV-associated diseases. These trials have utilized information on the precise location of viral epitopes for T cell recognition, for either measuring or enhancing responses. In this study, we have characterized the T cell response to the highly immunogenic BZLF1 antigen of EBV by greatly expanding the number of defined T cell epitopes. An unusual clustering of epitopes was identified, highlighting a small region of BZLF1 that is targeted by the immune response of a high proportion of the world's population. This focusing of the immune response could be utilized in developing vaccines/therapies with wide coverage, or it could potentially be exploited by the virus to escape the immune response.
人类白细胞抗原（HLA）基因座的多态性确保了 CD8(+)T 细胞对病毒的反应针对多种抗原表位，从而最大限度地减少了病毒在人群中逃逸突变的影响。EBV 的 BZLF1 抗原是 CD8(+)T 细胞的免疫优势靶标，但由于不完全的表位映射，仅在有限数量的 HLA 分子的背景下对该反应进行了描述。我们现在已经从 BZLF1 中大大扩展了定义明确的 CD8(+)T 细胞表位的数量，从而可以在更大比例的人群中评估该反应。抗原的一些区域不能被 CD8(+)T 细胞识别，而另一些区域则包含不同 HLA 分子呈递的重叠表位簇。BZLF1 的这些高度免疫原性区域包括多态性序列，以至于多达四个重叠表位受到世界不同地区常见的单个氨基酸变异的影响。这种将免疫反应集中在病毒蛋白的有限区域可能是由于与人类蛋白的序列相似性通过自身耐受而产生“免疫盲点”。这项研究极大地提高了对 BZLF1 免疫反应的理解，并且精确映射的 T 细胞表位可能直接用于疫苗开发和过继免疫治疗。
EBV 是一种重要的人类病原体，与包括鼻咽癌和霍奇金淋巴瘤在内的几种恶性肿瘤有关。T 淋巴细胞对于病毒控制至关重要，旨在操纵免疫系统这一部分的临床试验已经证明了在治疗这些 EBV 相关疾病方面的疗效。这些试验利用了关于 T 细胞识别病毒表位的确切位置的信息，用于测量或增强反应。在这项研究中，我们通过大大扩展定义明确的 T 细胞表位的数量，来描述 EBV 的高度免疫原性 BZLF1 抗原的 T 细胞反应。鉴定了一个不寻常的表位簇，突出了 BZLF1 的一个小区域，该区域是世界上很大一部分人口的免疫反应的靶标。这种免疫反应的集中可以用于开发具有广泛覆盖范围的疫苗/疗法，或者它可能被病毒利用来逃避免疫反应。
