HLA class I alleles are associated with peptide-binding repertoires of different size, affinity, and immunogenicity.
HLA class I alleles are associated with peptide-binding repertoires of different size, affinity, and immunogenicity.
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DOI：
10.4049/jimmunol.1302101
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发表时间：
2013-12-15
期刊：
影响因子：
--
通讯作者：
Sette A
中科院分区：
文献类型：
--
作者：
Paul S;Weiskopf D;Angelo MA;Sidney J;Peters B;Sette A
人类白细胞抗原结合亲和力的预测被广泛用于识别候选的T细胞表位，亲和力为500 nM通常被用作多肽选择的阈值。然而，预测与500 nm亲和力结合的多肽的比例(%)因等位基因而异。例如，在一个大约30,000个登革热病毒衍生多肽的大集合中，只有0.3%被预测与HLAA*0101结合，而近5%被预测与A*0201结合。这种显著的差异不能归因于所用算法的准确性的变化，因为预测值与体外测定的与纯化的人类白细胞抗原分子的亲和力密切相关。这些数据提出了一个问题，不同的等位基因是否也会在表位谱大小方面存在差异，即相关表位的数量，或者，等位基因是否会在与免疫原性相关的亲和力阈值方面有很大的差异。为了解决这一问题，用不同结合亲和力和相对百分位数排序的多肽免疫具有宽(A*0201)、中(B*0702)或窄(A*0101)谱系的转基因小鼠。结果表明，绝对结合能力是一个更好的免疫原性预测指标，对免疫表位数据库(IEDB)表位的分析表明，使用等位基因特异性亲和力阈值可以提高预测效果。最后，我们探讨了这一现象的遗传和结构基础。虽然没有定义严格的相关性，但平均而言，与HLAA等位基因相比，HLAB等位基因与显著狭窄的谱系相关。
Prediction of HLA binding affinity is widely utilized to identify candidate T cell epitopes, and an affinity of 500 nM is routinely used as a threshold for peptide selection. However, the fraction (%) of peptides predicted to bind with affinities of 500 nM varies by allele. For example, of a large collection of about 30,000 dengue virus derived peptides only 0.3% were predicted to bind HLA A*0101, while nearly 5% were predicted for A*0201. This striking difference could not be ascribed to variation in accuracy of the algorithms utilized, 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 (A*0201), intermediate (B*0702) 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 (IEDB) revealed that predictive efficacy is increased using allele-specific affinity thresholds. Finally, we investigate the genetic and structural basis of the phenomenon. While no stringent correlate was defined, on average HLA B alleles are associated with significantly narrower repertoires than HLA A alleles.
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