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

  • Cell Rep. 2017 May 16;19(7):1394-1405. doi: 10.1016/j.celrep.2017.04.059.
Hugo G Hilton  1 ,  Curtis P McMurtrey  2 ,  Alex S Han  3 ,  Zakia Djaoud  3 ,  Lisbeth A Guethlein  3 ,  Jeroen H Blokhuis  3 ,  Jason L Pugh  3 ,  Ana Goyos  3 ,  Amir Horowitz  3 ,  Rico Buchli  4 ,  Ken W Jackson  2 ,  Wilfred Bardet  2 ,  David A Bushnell  5 ,  Philip J Robinson  5 ,  Juan L Mendoza  6 ,  Michael E Birnbaum  6 ,  Morten Nielsen  7 ,  K Christopher Garcia  6 ,  William H Hildebrand  2 ,  Peter Parham  3
Affiliations
  • 1. Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
  • 2. Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
  • 3. Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
  • 4. Pure Protein LLC, Oklahoma City, OK 73104, USA.
  • 5. Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
  • 6. Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Molecular & Cellular Physiology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
  • 7. Department of Bio and Health Informatics, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark; Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, Buenos Aires, Argentina.
PMID: 28514659 DOI: 10.1016/j.celrep.2017.04.059
Abstract

HLA-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.

Keywords
HLA class I; KIR; antigen presentation; genetic polymorphism; host-pathogen interactions; mass spectrometry; modern human migration; peptidome.