脊椎动物中病原体特异性适应性免疫的关键成分是主要组织相容性复合物(MHC)分子呈递病原体衍生的抗原肽。在MHC基因观察到的过度多态性被广泛认为是由于需要识别不同的病原体,一个叫做病原体驱动的平衡选择的过程。该过程假设病原体在它们的肽-源自病原体蛋白质组的短肽库-方面不同,因此不同病原体选择具有不同肽结合特性的不同MHC变体。这里,我们在51.9Mio肽的综合数据集中测试了这一假设,来自36种代表性人类病原体的肽。引人注目的是,我们发现,在630例病原体间的成对比较中,39.7%的病原体没有产生单一的共享肽,只有1.8%的病原体对共享超过1%的肽.的确,所有肽的98.8%对于单一病原体物种是独特的。使用计算结合预测来表征321种常见人MHCI类变体的结合特异性,我们调查了MHC变体在来自不同病原体的结合肽方面的数量差异.我们的分析显示了针对特定病原体的特化特征,尤其是具有窄肽结合库的MHC变体。这支持了这样的假设,即这种挑剔的MHC变体可能在群体中维持,因为它们提供了针对特定病原体的优势。总的来说,我们的结果为在自然群体中观察到的MHC基因的过度等位基因多样性建立了关键选择因子,并阐明了MHC变体中可变肽结合库的进化.
A key component of pathogen-specific adaptive immunity in vertebrates is the presentation of pathogen-derived antigenic peptides by major histocompatibility complex (MHC) molecules. The excessive polymorphism observed at MHC genes is widely presumed to result from the need to recognize diverse pathogens, a process called pathogen-driven balancing selection. This process assumes that pathogens differ in their peptidomes-the pool of short peptides derived from the pathogen\'s proteome-so that different pathogens select for different MHC variants with distinct peptide-binding properties. Here, we tested this assumption in a comprehensive data set of 51.9 Mio peptides, derived from the peptidomes of 36 representative human pathogens. Strikingly, we found that 39.7% of the 630 pairwise comparisons among pathogens yielded not a single shared peptide and only 1.8% of pathogen pairs shared more than 1% of their peptides. Indeed, 98.8% of all peptides were unique to a single pathogen species. Using computational binding prediction to characterize the binding specificities of 321 common human MHC class-I variants, we investigated quantitative differences among MHC variants with regard to binding peptides from distinct pathogens. Our analysis showed signatures of specialization toward specific pathogens especially by MHC variants with narrow peptide-binding repertoires. This supports the hypothesis that such fastidious MHC variants might be maintained in the population because they provide an advantage against particular pathogens. Overall, our results establish a key selection factor for the excessive allelic diversity at MHC genes observed in natural populations and illuminate the evolution of variable peptide-binding repertoires among MHC variants.