Barouch D, Friede T, Stevanović S, Tussey L, Smith K, Rowland-Jones S, Braud V, McMichael A, Rammensee H G
Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
J Exp Med. 1995 Dec 1;182(6):1847-56. doi: 10.1084/jem.182.6.1847.
Nearly half of HLA-A2-positive individuals in African populations have a subtype of HLA-A2 other than the A0201 allele. We have isolated the common African HLA-A2 subtype genes from Epstein-Barr virus-transformed B cell lines and have established stable class I reduced transfectants expressing these alleles. We have studied the peptide binding and presentation properties of A0201, A0202, A0205, A0214, and A6901 by a combination of approaches: assaying direct binding of labeled synthetic peptides, studying the ability of antigen-specific cytotoxic T lymphocytes to recognize peptide-pulsed cells, and sequencing peptide pools and individual ligands eluted from cells. We find that A0201-restricted peptides can also bind to A0202 but do not bind strongly to the other alleles in this study. We show that some cytotoxic T lymphocytes can recognize all subtypes capable of binding an antigenic peptide, whereas others are subtype specific. Sequencing of eluted peptides reveals that A0202 has a similar peptide motif to A0201, but that A0205, A0214, and A*6901 have different motifs. These data strongly support a model in which residue 9 (Phe or Tyr) of the A2/A68/A69 molecules is a critical factor in determining the specificity of the B pocket of the major histocompatibility complex and the position 2 anchor residue of associated peptides. We conclude that a single-amino acid difference in the major histocompatibility complex can be sufficient to cause a dramatic change in the nature of bound peptides, implying that individuals with closely related HLA subtypes may present very different repertoires of antigenic peptides to T cells in an immune response. It is likely to be a general phenomenon that very similar class I subtypes will behave as functionally distinct HLA allotypes.
非洲人群中近一半的HLA - A2阳性个体拥有除A0201等位基因之外的HLA - A2亚型。我们从爱泼斯坦 - 巴尔病毒转化的B细胞系中分离出常见的非洲HLA - A2亚型基因，并建立了表达这些等位基因的稳定的I类减少转染细胞系。我们通过多种方法研究了A0201、A0202、A0205、A0214和A6901的肽结合和呈递特性：检测标记合成肽的直接结合、研究抗原特异性细胞毒性T淋巴细胞识别肽脉冲细胞的能力以及对从细胞中洗脱的肽库和单个配体进行测序。我们发现A0201限制的肽也能与A0202结合，但在本研究中与其他等位基因结合不强。我们表明，一些细胞毒性T淋巴细胞可以识别所有能够结合抗原肽的亚型，而其他细胞毒性T淋巴细胞则具有亚型特异性。洗脱肽的测序显示A0202与A0201具有相似的肽基序，但A0205、A0214和A*6901具有不同的基序。这些数据有力地支持了一个模型，其中A2/A68/A69分子的第9位残基（苯丙氨酸或酪氨酸）是决定主要组织相容性复合体B口袋特异性和相关肽的第2位锚定残基位置的关键因素。我们得出结论，主要组织相容性复合体中的单个氨基酸差异可能足以导致结合肽性质的显著变化，这意味着具有密切相关HLA亚型的个体在免疫反应中可能向T细胞呈递非常不同的抗原肽库。很可能是一种普遍现象，即非常相似的I类亚型将表现为功能上不同的HLA同种异型。
