Chen Haiwen, Zhang Xiao, Zhang Shanshan, Duan Xiaobing, Xiang Tong, Zhou Xiang, Zhang Wanlin, Zhang Xinyu, Feng Qisheng, Kang Yinfeng, Li Jiangping, Deng Lan, Wang Liang, Lv Xing, Zeng Musheng, Zeng Yi-Xin, Xu Miao
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
J Virol. 2021 Apr 26;95(10). doi: 10.1128/JVI.00081-21. Epub 2021 Mar 3.
Glycoprotein B (gB) is an essential fusion protein for the Epstein-Barr virus (EBV) infection of both B cells and epithelial cells and is thus a promising target antigen for a prophylactic vaccine to prevent or reduce EBV-associated disease. T cell responses play key roles in the control of persistent EBV infection and in the efficacy of a vaccine. However, to date, T cell responses to gB have been characterized for only a limited number of human leukocyte antigen (HLA) alleles. Here, we screened gB T cell epitopes in 23 healthy EBV carriers and ten patients with nasopharyngeal cancer (NPC) using a peptide library spanning the entire gB sequence. We identified twelve novel epitopes in the context of seven new HLA restrictions that are common in Asian populations. Two epitopes, gB and gB, restricted by HLA-B58:01 and B38:02, respectively, elicited specific CD8 T cell responses to inhibit EBV-driven B cell transformation. Interestingly, gB-specific CD8 T cells were more frequent in healthy viral carriers with EBV reactivation than in those without EBV reactivation, indicating that EBV reactivation stimulates both humoral (VCA-gp125-IgA) and cellular responses to gB. We further found that most gB epitopes are conserved among different EBV strains. Our study broadens the diversity and HLA restrictions of gB epitopes and suggests that gB is a common target of T cell responses in healthy viral carriers with EBV reactivation. In particular, the precisely mapped and conserved gB epitopes provide valuable information for prophylactic vaccine development.T cells are crucial for the control of persistent EBV infection and the development of EBV-associated diseases. The EBV gB protein is essential for virus entry into B cells and epithelial cells and is thus a target antigen for vaccine development. Understanding T cell responses to gB is important for subunit vaccine design. Herein, we comprehensively characterized T cell responses to full-length gB. Our results expand the available gB epitopes and HLA restrictions, particularly those common in Asian populations. Furthermore, we showed that gB-specific CD8 T cells inhibit B cell transformation and that gB-specific CD8 T cell responses may be associated with intermittent EBV reactivation in asymptomatic viral carriers. These gB epitopes are highly conserved among geographically separated EBV strains. Precisely mapped and conserved T cell epitopes may contribute to immune monitoring and to the development of a gB subunit vaccine.
糖蛋白B（gB）是爱泼斯坦-巴尔病毒（EBV）感染B细胞和上皮细胞所必需的融合蛋白，因此是预防或减少EBV相关疾病的预防性疫苗的一个有前景的靶抗原。T细胞反应在控制持续性EBV感染和疫苗效力方面发挥关键作用。然而，迄今为止，仅对有限数量的人类白细胞抗原（HLA）等位基因的gB T细胞反应进行了表征。在此，我们使用覆盖整个gB序列的肽库，在23名健康EBV携带者和10名鼻咽癌（NPC）患者中筛选了gB T细胞表位。我们在亚洲人群中常见的7种新的HLA限制条件下鉴定出12个新表位。分别受HLA-B58:01和B38:02限制的两个表位gB和gB，引发了特异性CD8 T细胞反应以抑制EBV驱动的B细胞转化。有趣的是，与未发生EBV再激活的健康病毒携带者相比，发生EBV再激活的健康病毒携带者中gB特异性CD8 T细胞更频繁，这表明EBV再激活刺激了针对gB的体液（VCA-gp125-IgA）和细胞反应。我们进一步发现，大多数gB表位在不同EBV毒株中是保守的。我们的研究拓宽了gB表位的多样性和HLA限制，并表明gB是发生EBV再激活的健康病毒携带者中T细胞反应的常见靶标。特别是，精确映射和保守的gB表位为预防性疫苗开发提供了有价值的信息。T细胞对于控制持续性EBV感染和EBV相关疾病的发展至关重要。EBV gB蛋白对于病毒进入B细胞和上皮细胞至关重要，因此是疫苗开发的靶抗原。了解T细胞对gB的反应对于亚单位疫苗设计很重要。在此，我们全面表征了对全长gB的T细胞反应。我们的结果扩展了可用的gB表位和HLA限制，特别是亚洲人群中常见的那些。此外，我们表明gB特异性CD8 T细胞抑制B细胞转化，并且gB特异性CD8 T细胞反应可能与无症状病毒携带者中间歇性EBV再激活有关。这些gB表位在地理上分离的EBV毒株中高度保守。精确映射和保守的T细胞表位可能有助于免疫监测和gB亚单位疫苗的开发。
