The impact of human leukocyte antigen (HLA) micropolymorphism on ligand specificity within the HLA-B*41 allotypic family

Abstract

The online version of this article has a Supplementary Appendix. BackgroundPolymorphic differences between human leukocyte antigen (HLA) molecules affect the specificity and conformation of their bound peptides and lead to differential selection of the T-cell repertoire. Mismatching during allogeneic transplantation can, therefore, lead to immunological reactions. Design and MethodsWe investigated the structure-function relationships of six members of the HLA-B*41 allelic group that differ by six polymorphic amino acids, including positions 80, 95, 97 and 114 within the antigen-binding cleft. Peptide-binding motifs for B*41:01, *41:02, *41:03, *41:04, *41:05 and *41:06 were determined by sequencing self-peptides from recombinant B*41 molecules by electrospray ionization tandem mass spectrometry. The crystal structures of HLA-B*41:03 bound to a natural 16-mer self-ligand (AEMYGSVTEHPSPSPL) and HLA-B*41:04 bound to a natural 11-mer self-ligand (HEEAVSVDRVL) were solved. ResultsPeptide analysis revealed that all B*41 alleles have an identical anchor motif at peptide position 2 (glutamic acid), but differ in their choice of C-terminal pΩ anchor (proline, valine, leucine). Additionally, B*41:04 displayed a greater preference for long peptides (>10 residues) when compared to the other B*41 allomorphs, while the longest peptide to be eluted from the allelic group (a 16mer) was obtained from B*41:03. The crystal structures of HLA-B*41:03 and HLA-B*41:04 revealed that both alleles interact in a highly conserved manner with the terminal regions of their respective ligands, while micropolymorphism-induced changes in the steric and electrostatic properties of the antigen-binding cleft account for differences in peptide repertoire and auxiliary anchoring. ConclusionsDifferences in peptide repertoire, and peptide length specificity reflect the significant functional evolution of these closely related allotypes and signal their importance in allogeneic transplantation, especially B*41:03 and B*41:04, which accommodate longer peptides, creating structurally distinct peptide-HLA complexes.

HIV Control through a Single Nucleotide on the HLA-B Locus

“…Previous studies of related HLA molecules differing by only a single amino acid support the findings presented here that apparently minor differences between HLA molecules may have a major impact on antiviral immunity (3,4,7,18,20,26,29,37,49,52). In relation to HLA-mediated control of HIV, we have previously demonstrated the increased repertoire of HIV-specific epitope peptides presented by HLA-B*57:03 compared to HLA-B*57:02, HLA molecules that differ by a single change at HLA residue 156 (Leu¡Arg).…”

HLA-B*57 Micropolymorphism Shapes HLA Allele-Specific Epitope Immunogenicity, Selection Pressure, and HIV Immune Control

“…(Table 2). Other studies of the HLA-B*41 family show how 6 HLA-B*41 subtypes, differing in 6 MHC I residues, present different peptides of various lengths and thereby create structurally distinct peptide-HLA complexes (4). These studies underline the consequences of HLA micropolymorphism changes in residues lining the peptide-binding groove.…”

Tapasin Facilitation of Natural HLA-A and -B Allomorphs Is Strongly Influenced by Peptide Length, Depends on Stability, and Separates Closely Related Allomorphs

“…A broad bottom-up approach with as many potential immunodominant epitopes as possible is hence desirable for selection of peptide epitopes for peptide-based vaccines. HLA-I binding of longer peptides (11-25 aa) has indeed been shown, and presentation efficiency was found to be equal or even greater as compared with shorter peptides (33,34). It has been proposed that crucial factors controlling what lengths of peptides are presented include Ag-processing variables, such as proteasomal cleavage products and TAP-peptide transport preferences (33).…”