The Intergenic Recombinant HLA-B *46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands.
Hilton, H. G., McMurtrey, C. P., Han, A. S., Djaoud, Z., Guethlein, L. A., Blokhuis, J. H., Pugh, J. L., Goyos, A., Horowitz, A., Buchli, R., Jackson, K. W., Bardet, W., Bushnell, D. A., Robinson, P. J., Mendoza, J. L., Birnbaum, M. E., Nielsen, M., Garcia, K. C., Hildebrand, W. H. and Parham, P.
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.
Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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.
Pure Protein LLC, Oklahoma City, OK 73104, USA.
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
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.
Department of Bio and Health Informatics, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark; Instituto de Investigaciones Biotecnologicas, Universidad Nacional de San Martin, Buenos Aires, Argentina.
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.
Cell Rep 19(7): 1394-1405 (2017)