Unique Pathogen Peptidomes Facilitate Pathogen-Specific Selection and Specialization of MHC Alleles

Abstract

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 dataset 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 towards 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.

Individual HLA heterogeneity and its implications for cellular immune evasion in cancer and beyond

“…The wide range of HLA polymorphisms currently present in human populations has been selected by evolutionary forces via a process of balancing selection, favoring alleles or allelic combinations able to sustain the burden of diverse pathogens to which human populations have been exposed to throughout their history ( 21 , 27 – 29 ) The extent of this genetic variation, mainly consisting in an increased rate of single nucleotide polymorphisms (SNPs), peaks within the antigen binding sites, resulting from natural selection favoring the diversification of peptide-binding capabilities ( 13 ). The basis for this pathogen-mediated selection is represented by the unique pathogen-specific antigen repertoires that hardly overlap among species, so that each pathogen species challenges the immune system in a different way ( 30 ).…”

HLA variants and TCR diversity against SARS-CoV-2 in the pre-COVID-19 era

“…2A). A dual role of HLA-A and B as generalists and specialists, respectively, has been discussed 12,13 . A significant correlation was observed between peptide overlap and HLA evolutionary divergence (HED) (mantel test, p<0.001, Fig.…”

COVID-19 Pandemic: Escape of Pathogenic Variants and MHC Evolution

“…This has led to support for the reflection on the maintenance and evolution of polymorphism. Current thinking is based on the ability of certain alleles to better recognize certain pathogens [ 16 , 17 ]. It should be noted that the hypotheses explaining the evolution and maintenance of polymorphism via the pathogen driven selection are still based on the same mechanism proposed in the 1970s—the heterozygous advantage, the advantage of rare alleles [ 1 ], and in the early 1990s—fluctuating selection [ 18 ].…”