Hoare Hilary L, Sullivan Lucy C, Pietra Gabriella, Clements Craig S, Lee Eleanor J, Ely Lauren K, Beddoe Travis, Falco Michela, Kjer-Nielsen Lars, Reid Hugh H, McCluskey James, Moretta Lorenzo, Rossjohn Jamie, Brooks Andrew G
The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
Nat Immunol. 2006 Mar;7(3):256-64. doi: 10.1038/ni1312. Epub 2006 Feb 12.
In contrast to antigen-specific immunity orchestrated by major histocompatibility complex (MHC) class Ia molecules, the ancestrally related nonclassical MHC class Ib molecules generally mediate innate immune responses. Here we have demonstrated the structural basis by which the MHC class Ib molecule HLA-E mediates an adaptive MHC-restricted cytotoxic T lymphocyte response to human cytomegalovirus. Highly constrained by host genetics, the response showed notable fine specificity for position 8 of the viral peptide, which is the sole discriminator of self versus nonself. Despite the evolutionary divergence of MHC class Ia and class Ib molecules, the structure of the T cell receptor-MHC class Ib complex was very similar to that of conventional T cell receptor-MHC class Ia complexes. These results emphasize the evolutionary 'ambiguity' of HLA-E, which not only interacts with innate immune receptors but also has the functional capacity to mediate virus-specific cytotoxic T lymphocyte responses during adaptive immunity.
与由主要组织相容性复合体（MHC）Ia类分子精心编排的抗原特异性免疫不同，具有共同祖先关系的非经典MHC Ib类分子通常介导先天性免疫反应。在此，我们展示了MHC Ib类分子HLA-E介导对人巨细胞病毒的适应性MHC限制性细胞毒性T淋巴细胞反应的结构基础。该反应受到宿主遗传学的高度限制，对病毒肽的第8位表现出显著的精细特异性，这是区分自我与非自我的唯一因素。尽管MHC Ia类和Ib类分子在进化上存在差异，但T细胞受体-MHC Ib类复合体的结构与传统的T细胞受体-MHC Ia类复合体非常相似。这些结果强调了HLA-E在进化上的“模糊性”，它不仅与先天性免疫受体相互作用，而且在适应性免疫过程中具有介导病毒特异性细胞毒性T淋巴细胞反应的功能能力。
