Affiliations | Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia; Departments of Structural Biology and Microbiology & Immunology, School of Medicine, Stanford University, Stanford, 94305, CA, USA; Calico Life Sciences LLC, South San Francisco, 94080, CA, USA; Department of Genetics, School of Medicine, Stanford University, Stanford, 94305, CA, USA; Department of Molecular and Cellular Physiology, School of Medicine, Stanford University, Stanford, 94305, CA, USA; Institute for Molecular Engineering and Department of Biochemistry & Molecular Biology, University of Chicago, Chicago, 60637, IL, USA; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, 3010, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK; Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Mon... | |
Abstract | 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. | |