HLA-B57 micropolymorphism defines the sequence and conformational breadth of the immunopeptidome

Abstract

Immunophenotypic differences between closely related human leukocyte antigen (HLA) alleles have been associated with divergent clinical outcomes in infection, autoimmunity, transplantation and drug hypersensitivity. Here we explore the impact of micropolymorphism on peptide antigen presentation by three closely related HLA molecules, HLA-B*57:01, HLA-B*57:03 and HLA-B*58:01, that are differentially associated with the HIV elite controller phenotype and adverse drug reactions. For each allotype, we mine HLA ligand data sets derived from the same parental cell proteome to define qualitative differences in peptide presentation using classical peptide binding motifs and an unbiased statistical approach. The peptide repertoires show marked qualitative overlap, with 982 peptides presented by all allomorphs. However, differences in peptide abundance, HLA-peptide stability, and HLA-bound conformation demonstrate that HLA micropolymorphism impacts more than simply the range of peptide ligands. These differences provide grounds for distinct immune reactivity and insights into the capacity of micropolymorphism to diversify immune outcomes.

The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function

“…For example, in the LF9 and LY9 peptides, the lysine and arginine at PΩ-2 were fully accommodated in the E pocket of HLA-B*57:01 but were surface exposed when complexed with HLA-B*57:03. This same switch in the conformation of the PΩ-2 residue in peptides bound to HLA-B*57:01 and HLA-B*57:03 has also been observed for the LTVQVARVW and LSSPVTKSW [LF9(W9)] peptides, indicative of characteristic differences between these closely related HLA class I allotypes (2). Critically, this altered conformation of the PΩ-2 side chain markedly impacted the capacity of KIR3DL1 to bind each HLA-B57 molecule as assessed by both tetramer-binding analyses and SPR.…”

“…Indeed, each pair of HLA-B57 tetramers with a given peptide bound to LILRB1 similarly, with the exception of LY9 in the context of HLA-B*57:03 that consistently bound to LILRB1 more efficiently than HLA-B*57:01/ LY9, possibly reflecting intrinsic differences in the stability of this HLA/peptide complex. Indeed, HLA-B*57:03/LY9 is reportedly less stable than HLA-B*57:01/LY9 whereas the thermostabilities of LF9 and LF9(W9) bound to the two HLA-B57 molecules are more similar (2). Thus, the data suggest that, despite potential differences in the intrinsic affinity of each peptide for the HLA class I allotypes, both HLA-B57 allotypes could nevertheless be refolded with each peptide allowing for generation of tetramers of sufficient stability to allow us to compare their binding to KIR3DL1.…”

“…This polymorphism impacts both the nature of the peptide-binding cleft and the surface features displayed to both innate and adaptive immune receptors. While major allotypic groupings of HLA class I may differ by 20 to 30 amino acids in these regions (1), there are numerous closely related HLA allotypes that exhibit micropolymorphisms, differing by as few as one or two amino acids (2,3). While these closely related HLA allotypes frequently bind overlapping sets of peptides, these subtle polymorphisms can nevertheless profoundly impact T cell receptor (TCR) recognition, tapasin dependence, deletional tolerance during T cell development, T cell alloreactivity, and drug hypersensitivity reactions (3)(4)(5)(6)(7)(8)(9).…”

Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides

“…Interestingly, peptides with C-terminal tryptophan had the highest predicted HLA-binding affinity (<50 nM). Although arginine was dominant at P7 [a secondary anchor residue ( 21 )] of high-affinity peptides, glutamic acid was significantly increased in peptides of FLX-cells ( Figure 4C and Tables S2A, B ). These findings suggest that, in contrast to the ability of abacavir to alter the anchor motif of the neoepitopes from phenylalanine, tryptophan or tyrosine to leucine or isoleucine at PΩ, FLX increases the presentation of self-epitopes with predominantly tryptophan at the C-terminal position.…”

Conserved epitopes with high HLA-I population coverage are targets of CD8+ T cells associated with high IFN-γ responses against all dengue virus serotypes

“…The selection criteria for conserved epitopes shown in Table 1 were: (i) experimentally tested with positive response in all 4 serotypes from the IEDB data base; (ii) a maximum of 2 amino acid mutations between the epitope sequences across the four serotypes. Anchor positions of these epitopes were retrieved from the peptide-MHC binding motif data from IEDB resources and published data [34][35][36][37][38] .…”