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

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

doi:10.1016/j.celrep.2017.04.059

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.

Authors

Hugo G Hilton¹, Curtis P McMurtrey², Alex S Han³, Zakia Djaoud³, Lisbeth A Guethlein³, Jeroen H Blokhuis³, Jason L Pugh³, Ana Goyos³, Amir Horowitz³, Rico Buchli⁴, Ken W Jackson², Wilfred Bardet², David A Bushnell⁵, Philip J Robinson⁵, Juan L Mendoza⁶, Michael E Birnbaum⁶, Morten Nielsen⁷, K Christopher Garcia⁶, William H Hildebrand², Peter Parham³

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: hghhilton@gmail.com.
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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs
Cytotoxicity, Immunologic
HLA-B Antigens / chemistry
HLA-B Antigens / metabolism*
HLA-C Antigens
Humans
Killer Cells, Natural / immunology
Ligands
Models, Biological
Peptides / metabolism*
Protein Binding
Proteome / metabolism*
Receptors, KIR2DL3 / metabolism*
Recombination, Genetic / genetics

Substances

HLA-B Antigens
HLA-B46 antigen
HLA-C Antigens
Ligands
Peptides
Proteome
Receptors, KIR2DL3

Abstract

Publication types

MeSH terms

Substances

Grants and funding