Cell Reports
(May 2017)
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
Affiliations
Hugo G. Hilton
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Curtis P. McMurtrey
Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Alex S. Han
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Zakia Djaoud
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Lisbeth A. Guethlein
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Jeroen H. Blokhuis
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Jason L. Pugh
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Ana Goyos
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Amir Horowitz
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Rico Buchli
Pure Protein LLC, Oklahoma City, OK 73104, USA
Ken W. Jackson
Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Wilfred Bardet
Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
David A. Bushnell
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Philip J. Robinson
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Juan L. Mendoza
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Michael E. Birnbaum
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Morten Nielsen
Department of Bio and Health Informatics, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
K. Christopher Garcia
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
William H. Hildebrand
Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Peter Parham
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
DOI
https://doi.org/10.1016/j.celrep.2017.04.059
Journal volume & issue
Vol. 19,
no. 7
Abstract
Read online
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.
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