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

• Published in: Cell reports (Cambridge) Vol. 19; no. 7; pp. 1394 - 1405
• Main Authors: Hilton, Hugo G., McMurtrey, Curtis P., Han, Alex S., Djaoud, Zakia, Guethlein, Lisbeth A., Blokhuis, Jeroen H., Pugh, Jason L., Goyos, Ana, Horowitz, Amir, Buchli, Rico, Jackson, Ken W., Bardet, Wilfred, Bushnell, David A., Robinson, Philip J., Mendoza, Juan L., Birnbaum, Michael E., Nielsen, Morten, Garcia, K. Christopher, Hildebrand, William H., Parham, Peter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.05.2017; The Author(s); Elsevier
• Subjects: Amino Acid Motifs; antigen presentation; Cytotoxicity, Immunologic; genetic polymorphism; HLA class I; HLA-B Antigens - chemistry; HLA-B Antigens - metabolism; HLA-C Antigens; host-pathogen interactions; Humans; Killer Cells, Natural - immunology; KIR; Ligands; mass spectrometry; Models, Biological; modern human migration; Peptides - metabolism; peptidome; Protein Binding; Proteome - metabolism; Receptors, KIR2DL3 - metabolism; Recombination, Genetic - genetics; host-pathogen interactions; antigen presentation; KIR; HLA class I; peptidome; mass spectrometry; genetic polymorphism; modern human migration
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.04.059

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. [Display omitted] •The interlocus recombinant HLA-B∗46:01 is found at high frequency in Southeast Asia•HLA-B∗46:01 has a low-diversity peptidome that is distinct from both its parents•A subset of HLA-B∗46:01 peptides provides ligands for the NK cell receptor KIR2DL3•The unique features of HLA-B∗46:01 correlate with protection against leprosy Hilton et al. show how the recombination that formed HLA-B∗46:01 endowed it with a distinctive peptidome and unique functional properties. These properties likely protect carriers from severe infection with Mycobacterium leprae, the cause of leprosy, and they may account for the high frequency of HLA-B∗46:01 in Southeast Asia.