Division of Genetics & Development, Toronto Western Research Institute, Toronto, Ontario, Canada M5T-2S8; Institute of Medical Sciences, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada M5S 1A8; Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8; and.
Division of Genetics & Development, Toronto Western Research Institute, Toronto, Ontario, Canada M5T-2S8;
J Immunol. 2014 Jun 15;192(12):5520-8. doi: 10.4049/jimmunol.1400343. Epub 2014 May 16.
Endoplasmic reticulum-associated aminopeptidase-1 (ERAP1) plays a critical role in the processing of peptides prior to binding to MHC class I molecules. In this article, we show for the first time, to our knowledge, that the HLA-B27 immunodominant influenza nucleoprotein (NP) 383-391 epitope is made as an N-terminally extended 14-mer before it is trimmed by ERAP. In the absence of ERAP, there is a significant reduction in the CTL response to the B27/NP383-391 epitope in influenza A (flu)-infected B27/ERAP(-/-) mice. With the use of tetramer staining, the number of naive CD8(+) T cells expressing TCR Vβ8.1 in B27/ERAP(-/-) transgenic mice is significantly lower than that seen in B27/ERAP(+/+) mice. HLA-B27 surface expression in naive and flu-infected B27/ERAP(-/-) mice is also lower than the expression seen for the same allele in naive and flu-infected B27/ERAP(+/+) mice. In contrast, surface expression of HLA-B7 was unaffected by the absence of ERAP in B7/ERAP(-/-) transgenic mice. The B7-restricted NP418-426 CTL response in flu-infected B7/ERAP(-/-) and B7/ERAP(+/+) mice was also similar. These results provide, to our knowledge, the first in vivo demonstration of ERAP functionally influencing host immune response in an HLA allele-specific manner. This principle has relevance to diseases such as ankylosing spondylitis, in which HLA-B27 and ERAP jointly contribute to disease predisposition.
内质网相关氨肽酶 1（ERAP1）在肽与 MHC Ⅰ类分子结合之前的加工中起着关键作用。在本文中，我们首次表明，据我们所知，HLA-B27 免疫优势流感核蛋白（NP）383-391 表位在被 ERAP 修剪之前作为 N 端延伸的 14 肽产生。在缺乏 ERAP 的情况下，感染流感的 B27/ERAP(-/-)小鼠中针对 B27/NP383-391 表位的 CTL 反应显著减少。使用四聚体染色，B27/ERAP(-/-)转基因小鼠中表达 TCR Vβ8.1 的幼稚 CD8(+)T 细胞数量明显低于 B27/ERAP(+/+)小鼠。B27/ERAP(-/-)和 B27/ERAP(+/+)小鼠中，HLA-B27 在未感染和感染流感的细胞表面的表达也低于相同等位基因在未感染和感染流感的细胞中的表达。相比之下，在 B7/ERAP(-/-)转基因小鼠中，缺乏 ERAP 对 HLA-B7 的表面表达没有影响。在感染流感的 B7/ERAP(-/-)和 B7/ERAP(+/+)小鼠中，B7 限制性 NP418-426 CTL 反应也相似。这些结果首次提供了体内证据，证明 ERAP 以 HLA 等位基因特异性的方式对宿主免疫反应产生功能性影响。这一原则与强直性脊柱炎等疾病有关，在这些疾病中，HLA-B27 和 ERAP 共同导致疾病易感性。
