CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, China.
Sci Rep. 2016 Sep 16;6:33612. doi: 10.1038/srep33612.
HLA class I (HLA-I) transgenic mice have proven to be useful models for studying human MHC-related immune responses over the last two decades. However, differences in the processing and presentation machinery between humans and mice may have profound effects on HLA-I restricted antigen presentation. In this study, we generated a novel human TAP-LMP (hTAP-LMP) gene cluster transgenic mouse model carrying an intact human TAP complex and two human immunoproteasome LMP subunits, PSMB8/PSMB9. By crossing the hTAP-LMP strain with different HLA-I transgenic mice, we found that the expression levels of human HLA-I molecules, especially the A3 supertype members (e.g., A11 and A33), were remarkably enhanced in corresponding HLA-I/hTAP-LMP transgenic mice. Moreover, we found that humanized processing and presentation machinery increased antigen presentation of HLA-A11-restricted epitopes and promoted the rapid reduction of hepatitis B virus (HBV) infection in HLA-A11/hTAP-LMP mice. Together, our study highlights that HLA-I/hTAP-LMP mice are an improved model for studying antigen presentation of HLA-I molecules and their related CTL responses.
在过去的二十年中，HLA-I 类转基因小鼠已被证明是研究人类 MHC 相关免疫反应的有用模型。然而，人类和小鼠之间加工和呈递机制的差异可能对 HLA-I 类限制的抗原呈递产生深远的影响。在这项研究中，我们构建了一种新型的人 TAP-LMP（hTAP-LMP）基因簇转基因小鼠模型，该模型携带完整的人 TAP 复合物和两个人类免疫蛋白酶体 LMP 亚基 PSMB8/PSMB9。通过将 hTAP-LMP 株与不同的 HLA-I 转基因小鼠杂交，我们发现相应的 HLA-I/hTAP-LMP 转基因小鼠中人类 HLA-I 分子的表达水平，特别是 A3 超型成员（例如 A11 和 A33），显著增强。此外，我们发现，人源化的加工和呈递机制增加了 HLA-A11 限制性表位的抗原呈递，并促进了 HLA-A11/hTAP-LMP 小鼠中乙型肝炎病毒（HBV）感染的快速减少。总之，我们的研究强调了 HLA-I/hTAP-LMP 小鼠是研究 HLA-I 分子及其相关 CTL 反应的抗原呈递的改良模型。
