PMID- 30410026 OWN - NLM STAT- MEDLINE DCOM- 20190503 LR - 20191108 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 9 IP - 1 DP - 2018 Nov 8 TI - HLA-B57 micropolymorphism defines the sequence and conformational breadth of the immunopeptidome. PG - 4693 LID - 10.1038/s41467-018-07109-w [doi] LID - 4693 AB - Immunophenotypic differences between closely related human leukocyte antigen (HLA) alleles have been associated with divergent clinical outcomes in infection, autoimmunity, transplantation and drug hypersensitivity. Here we explore the impact of micropolymorphism on peptide antigen presentation by three closely related HLA molecules, HLA-B*57:01, HLA-B*57:03 and HLA-B*58:01, that are differentially associated with the HIV elite controller phenotype and adverse drug reactions. For each allotype, we mine HLA ligand data sets derived from the same parental cell proteome to define qualitative differences in peptide presentation using classical peptide binding motifs and an unbiased statistical approach. The peptide repertoires show marked qualitative overlap, with 982 peptides presented by all allomorphs. However, differences in peptide abundance, HLA-peptide stability, and HLA-bound conformation demonstrate that HLA micropolymorphism impacts more than simply the range of peptide ligands. These differences provide grounds for distinct immune reactivity and insights into the capacity of micropolymorphism to diversify immune outcomes. FAU - Illing, Patricia T AU - Illing PT AUID- ORCID: 0000-0002-3870-0796 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. FAU - Pymm, Phillip AU - Pymm P AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. AD - Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia. FAU - Croft, Nathan P AU - Croft NP AUID- ORCID: 0000-0002-2128-5127 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. FAU - Hilton, Hugo G AU - Hilton HG AD - Departments of Structural Biology and Microbiology & Immunology, School of Medicine, Stanford University, Stanford, 94305, CA, USA. AD - Calico Life Sciences LLC, South San Francisco, 94080, CA, USA. FAU - Jojic, Vladimir AU - Jojic V AD - Calico Life Sciences LLC, South San Francisco, 94080, CA, USA. FAU - Han, Alex S AU - Han AS AD - Department of Genetics, School of Medicine, Stanford University, Stanford, 94305, CA, USA. FAU - Mendoza, Juan L AU - Mendoza JL AD - Department of Molecular and Cellular Physiology, School of Medicine, Stanford University, Stanford, 94305, CA, USA. AD - Institute for Molecular Engineering and Department of Biochemistry & Molecular Biology, University of Chicago, Chicago, 60637, IL, USA. FAU - Mifsud, Nicole A AU - Mifsud NA AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. FAU - Dudek, Nadine L AU - Dudek NL AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. FAU - McCluskey, James AU - McCluskey J AUID- ORCID: 0000-0002-8597-815X AD - Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, 3010, Australia. FAU - Parham, Peter AU - Parham P AD - Departments of Structural Biology and Microbiology & Immunology, School of Medicine, Stanford University, Stanford, 94305, CA, USA. FAU - Rossjohn, Jamie AU - Rossjohn J AUID- ORCID: 0000-0002-2020-7522 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. AD - Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia. AD - Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK. FAU - Vivian, Julian P AU - Vivian JP AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. julian.vivian@monash.edu. AD - Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia. julian.vivian@monash.edu. FAU - Purcell, Anthony W AU - Purcell AW AUID- ORCID: 0000-0003-0532-8331 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. anthony.purcell@monash.edu. LA - eng GR - K01 CA175127/CA/NCI NIH HHS/United States GR - R01 AI022039/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20181108 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (HLA-B Antigens) RN - 0 (HLA-B57 antigen) RN - 0 (Ligands) RN - 0 (Peptides) RN - 0 (Proteome) SB - IM MH - Amino Acid Motifs MH - Amino Acid Sequence MH - Base Sequence MH - Cell Line MH - HLA-B Antigens/chemistry/*genetics MH - Ligands MH - Models, Molecular MH - Peptides/chemistry/*metabolism MH - *Polymorphism, Genetic MH - Protein Binding MH - Protein Conformation MH - Protein Stability MH - Proteome/chemistry/*metabolism MH - T-Lymphocytes/metabolism PMC - PMC6224591 COIS- The authors declare no competing interests. EDAT- 2018/11/10 06:00 MHDA- 2019/05/06 06:00 PMCR- 2018/11/08 CRDT- 2018/11/10 06:00 PHST- 2017/08/08 00:00 [received] PHST- 2018/10/12 00:00 [accepted] PHST- 2018/11/10 06:00 [entrez] PHST- 2018/11/10 06:00 [pubmed] PHST- 2019/05/06 06:00 [medline] PHST- 2018/11/08 00:00 [pmc-release] AID - 10.1038/s41467-018-07109-w [pii] AID - 7109 [pii] AID - 10.1038/s41467-018-07109-w [doi] PST - epublish SO - Nat Commun. 2018 Nov 8;9(1):4693. doi: 10.1038/s41467-018-07109-w.