Shirai M, Arichi T, Nishioka M, Nomura T, Ikeda K, Kawanishi K, Engelhard V H, Feinstone S M, Berzofsky J A
Third Department of Internal Medicine, Kagawa Medical School, Japan.
J Immunol. 1995 Mar 15;154(6):2733-42.
Vaccine development in animal models depends on ability to recognize epitopes seen by human T cells. In this work, we show that CTL responses in transgenic mice expressing human HLA-A2.1 prospectively predict the same four of 11 hepatitis C virus (HCV) structural protein-derived peptides, expressing a sequence motif for HLA-A2.1 binding, that are actually recognized by human A2.1-restricted CTLs. The CTLs also recognized targets endogenously expressing these proteins. Human CTLs from HCV-infected patients, tested by using the same peptides, revealed a virtually identical response repertoire. A highly conserved HCV core peptide was the most immunogenic, and may be a valuable component of a vaccine against a broad range of HCV isolates in HLA-A2-positive patients. These results suggest that, in spite of species differences, the T cell repertoire is plastic enough to allow a similar response when the same class I MHC molecule is presenting the peptide. Thus, the HLA molecule plays the primary role in determining which peptides are recognized by CTLs. This transgenic mouse model is important for the study of HLA-restricted CTL determinants and for an approach to design a potential HCV vaccine.
动物模型中的疫苗开发取决于识别人类T细胞所识别表位的能力。在本研究中，我们发现，表达人类HLA - A2.1的转基因小鼠中的CTL反应可前瞻性地预测11种丙型肝炎病毒（HCV）结构蛋白衍生肽中的相同4种，这些肽表达了HLA - A2.1结合的序列基序，实际上被人类A2.1限制性CTL识别。这些CTL还识别内源性表达这些蛋白的靶标。使用相同肽对HCV感染患者的人类CTL进行检测，结果显示出几乎相同的反应谱。一种高度保守的HCV核心肽具有最强的免疫原性，可能是针对HLA - A2阳性患者中广泛的HCV分离株的疫苗的重要组成部分。这些结果表明，尽管存在物种差异，但当同一I类MHC分子呈递肽时，T细胞库具有足够的可塑性以产生相似的反应。因此，HLA分子在决定哪些肽被CTL识别方面起主要作用。这种转基因小鼠模型对于研究HLA限制性CTL决定簇以及设计潜在的HCV疫苗的方法具有重要意义。
