Liu Su-Dong, Su Jin, Zhang Shi-Meng, Dong Hai-Ping, Wang Hui, Luo Wei, Wen Qian, He Jian-Chun, Yang Xiao-Fan, Ma Li
Institute of Molecular Immunology, School of Biotechnology, Southern Medical University, Guangzhou, China.
Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
J Cell Mol Med. 2016 Sep;20(9):1718-28. doi: 10.1111/jcmm.12867. Epub 2016 Apr 12.
New vaccines are needed to combat Mycobacterium tuberculosis (MTB) infections. The currently employed Bacillus Calmette-Guérin vaccine is becoming ineffective, due in part to the emergence of multidrug-resistant tuberculosis (MDR-TB) strains and the reduced immune capacity in cases of HIV coinfection. CD8(+) T cells play an important role in the protective immunity against MTB infections, and the identification of immunogenic CD8(+) T cell epitopes specific for MTB is essential for the design of peptide-based vaccines. To identify CD8(+) T cell epitopes of MTB proteins, we screened a set of 94 MTB antigens for HLA class I A11:01-binding motifs. HLA-A11:01 is one of the most prevalent HLA molecules in Southeast Asians, and definition of T cell epitopes it can restrict would provide significant coverage for the Asian population. Peptides that bound with high affinity to purified HLA molecules were subsequently evaluated in functional assays to detect interferon-γ release and CD8(+) T cell proliferation in active pulmonary TB patients. We identified six novel epitopes, each derived from a unique MTB antigen, which were recognized by CD8(+) T cells from active pulmonary TB patients. In addition, a significant level of epitope-specific T cells could be detected ex vivo in peripheral blood mononuclear cells from active TB patients by an HLA-A*11:01 dextramer carrying the peptide Rv3130c194-204 (from the MTB triacylglycerol synthase Tgs1), which was the most frequently recognized epitope in our peptide library. In conclusion, this study identified six dominant CD8(+) T cell epitopes that may be considered potential targets for subunit vaccines or diagnostic strategies against TB.
需要新型疫苗来对抗结核分枝杆菌(MTB)感染。目前使用的卡介苗正变得无效,部分原因是多药耐药结核病(MDR-TB)菌株的出现以及HIV合并感染情况下免疫能力的下降。CD8(+) T细胞在抗MTB感染的保护性免疫中发挥重要作用,鉴定MTB特异性的免疫原性CD8(+) T细胞表位对于基于肽的疫苗设计至关重要。为了鉴定MTB蛋白的CD8(+) T细胞表位,我们筛选了一组94种MTB抗原以寻找HLA I类A11:01结合基序。HLA-A11:01是东南亚最常见的HLA分子之一,确定其能够限制的T细胞表位可为亚洲人群提供显著的覆盖范围。随后,在功能试验中评估与纯化的HLA分子高亲和力结合的肽,以检测活动性肺结核患者中干扰素-γ的释放和CD8(+) T细胞增殖。我们鉴定出六个新表位,每个表位都源自一种独特的MTB抗原,这些表位被活动性肺结核患者的CD8(+) T细胞识别。此外,通过携带肽Rv3130c194-204(来自MTB三酰甘油合酶Tgs1)的HLA-A*11:01四聚体,可在体外从活动性肺结核患者的外周血单核细胞中检测到显著水平的表位特异性T细胞,该肽是我们肽库中最常被识别的表位。总之,本研究鉴定出六个主要的CD8(+) T细胞表位,这些表位可被视为亚单位疫苗或结核病诊断策略的潜在靶点。