The Intergenic Recombinant HLA-B∗46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands

Hugo G Hilton,William H Hildebrand,Jason L Pugh,Alex S Han,Lisbeth A Guethlein,Ken W Jackson,Peter Parham,Michael E Birnbaum,Philip J Robinson,Ana Goyos,Rico Buchli,Amir Horowitz,Morten Nielsen,Jeroen H Blokhuis,Juan L Mendoza,Zakia Djaoud,Curtis P Mcmurtrey,Wilfried Bardet ,David Bushnell ,K Christopher García

doi:10.1016/j.celrep.2017.04.059

Abstract

SummaryHLA-B∗46:01 was formed by an intergenic mini-conversion, between HLA-B∗15:01 and HLA-C∗01:02, in Southeast Asia during the last 50,000 years, and it has since become the most common HLA-B allele in the region. A functional effect of the mini-conversion was introduction of the C1 epitope into HLA-B∗46:01, making it an exceptional HLA-B allotype that is recognized by the C1-specific natural killer (NK) cell receptor KIR2DL3. High-resolution mass spectrometry showed that HLA-B∗46:01 has a low-diversity peptidome that is distinct from those of its parents. A minority (21%) of HLA-B∗46:01 peptides, with common C-terminal characteristics, form ligands for KIR2DL3. The HLA-B∗46:01 peptidome is predicted to be enriched for peptide antigens derived from Mycobacterium leprae. Overall, the results indicate that the distinctive peptidome and functions of HLA-B∗46:01 provide carriers with resistance to leprosy, which drove its rapid rise in frequency in Southeast Asia.

Highlights

Population expansion, cultural changes, and migration during the last 100,000 years exposed humans to pathogens against which they had not evolved effective resistance
HLA-B*46:01, HLA-B*15:01, and HLA-C*01:02 Have Distinctive Peptidomes To compare the peptides bound by HLA-B*46:01 and its parental allotypes, we isolated these HLA molecules, eluted the bound peptides, and determined their sequences by mass spectrometry
We identified 6,387 peptides for HLA-B*15:01, 788 for HLA-C*01:02, and 2,115 for HLA-B*46:01 (Figure 1A)

Summary

Introduction

Population expansion, cultural changes, and migration during the last 100,000 years exposed humans to pathogens against which they had not evolved effective resistance. HLA-A, -B, and -C arose by a series of gene duplications from a common ancestral MHC class I gene (Parham et al, 1995) These genes serve as a reservoir of polymorphic sequences that can be recombined to create new HLA alleles that can provide protection against emerging pathogens. Such new variants are thought to arise in human populations during episodes of Darwinian selection, there is little direct evidence for the nature of the process. HLA-B*46:01 provides a compelling example of such an episode

Results

Discussion

Conclusion