Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
J Immunol. 2013 Dec 15;191(12):5831-9. doi: 10.4049/jimmunol.1302101. Epub 2013 Nov 4.
Prediction of HLA binding affinity is widely used to identify candidate T cell epitopes, and an affinity of 500 nM is routinely used as a threshold for peptide selection. However, the fraction (percentage) of peptides predicted to bind with affinities of 500 nM varies by allele. For example, of a large collection of ~30,000 dengue virus-derived peptides only 0.3% were predicted to bind HLA A0101, whereas nearly 5% were predicted for A0201. This striking difference could not be ascribed to variation in accuracy of the algorithms used, as predicted values closely correlated with affinity measured in vitro with purified HLA molecules. These data raised the question whether different alleles would also vary in terms of epitope repertoire size, defined as the number of associated epitopes or, alternatively, whether alleles vary drastically in terms of the affinity threshold associated with immunogenicity. To address this issue, strains of HLA transgenic mice with wide (A0201), intermediate (B0702), or narrow (A*0101) repertoires were immunized with peptides of varying binding affinity and relative percentile ranking. The results show that absolute binding capacity is a better predictor of immunogenicity, and analysis of epitopes from the Immune Epitope Database revealed that predictive efficacy is increased using allele-specific affinity thresholds. Finally, we investigated the genetic and structural basis of the phenomenon. Although no stringent correlate was defined, on average HLA B alleles are associated with significantly narrower repertoires than are HLA A alleles.
预测 HLA 结合亲和力被广泛用于鉴定候选 T 细胞表位，通常将 500 nM 的亲和力用作肽选择的阈值。然而，预测与 500 nM 亲和力结合的肽的分数（百分比）因等位基因而异。例如，在大量约 30000 个登革热病毒衍生肽中，只有 0.3%被预测与 HLA A0101 结合，而对于 A0201，近 5%被预测。这种显著差异不能归因于所用算法的准确性变化，因为预测值与用纯化 HLA 分子在体外测量的亲和力密切相关。这些数据提出了一个问题，即不同的等位基因是否也会在表位库大小（定义为相关表位的数量）方面有所不同，或者等位基因在与免疫原性相关的亲和力阈值方面是否存在巨大差异。为了解决这个问题，使用具有广泛（A0201）、中等（B0702）或狭窄（A*0101）库的 HLA 转基因小鼠系进行免疫，用具有不同结合亲和力和相对百分比排名的肽进行免疫。结果表明，绝对结合能力是免疫原性的更好预测因子，并且对免疫原数据库中的表位分析表明，使用等位基因特异性亲和力阈值可提高预测效果。最后，我们研究了这种现象的遗传和结构基础。尽管没有明确的相关性定义，但平均而言，HLA B 等位基因与明显较窄的库相关，而 HLA A 等位基因则与较宽的库相关。
