PMID- 36605212 OWN - NLM STAT- MEDLINE DCOM- 20230110 LR - 20230118 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes. PG - 1067463 LID - 10.3389/fimmu.2022.1067463 [doi] LID - 1067463 AB - Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and code for proteins that play a key role in guiding adaptive immune responses by presenting foreign and self peptides (ligands) to T cells. Each person carries up to 6 HLA class I variants (maternal and paternal copies of HLA-A, HLA-B and HLA-C genes) and also multiple HLA class II variants, which cumulatively define the landscape of peptides presented to T cells. Each HLA variant has its own repertoire of presented peptides with a certain sequence motif which is mainly defined by peptide anchor residues (typically the second and the last positions for HLA class I ligands) forming key interactions with the peptide-binding groove of HLA. In this study, we aimed to characterize HLA binding preferences in terms of molecular functions of presented proteins. To focus on the ligand presentation bias introduced specifically by HLA-peptide interaction we performed large-scale in silico predictions of binding of all peptides from human proteome for a wide range of HLA variants and established which functions are characteristic for proteins that are more or less preferentially presented by different HLA variants using statistical calculations and gene ontology (GO) analysis. We demonstrated marked distinctions between HLA variants in molecular functions of preferentially presented proteins (e.g. some HLA variants preferentially present membrane and receptor proteins, while others - ribosomal and DNA-binding proteins) and reduced presentation of extracellular matrix and collagen proteins by the majority of HLA variants. To explain these observations we demonstrated that HLA preferentially presents proteins enriched in amino acids which are required as anchor residues for the particular HLA variant. Our observations can be extrapolated to explain the protective effect of certain HLA alleles in infectious diseases, and we hypothesize that they can also explain susceptibility to certain autoimmune diseases and cancers. We demonstrate that these differences lead to differential presentation of HIV, influenza virus, SARS-CoV-1 and SARS-CoV-2 proteins by various HLA alleles. Taking into consideration that HLA alleles are inherited in haplotypes, we hypothesized that haplotypes composed of a combination of HLA variants with different presentation preferences should be more advantageous as they allow presenting a larger repertoire of peptides and avoiding holes in immunopeptidome. Indeed, we demonstrated that HLA-A/HLA-B and HLA-A/HLA-C haplotypes which have a high frequency in the human population are comprised of HLA variants that are more distinct in terms of functions of preferentially presented proteins than the control pairs. CI - Copyright (c) 2022 Karnaukhov, Paes, Woodhouse, Partridge, Nicastri, Brackenridge, Shcherbinin, Chudakov, Zvyagin, Ternette, Koohy, Borrow and Shugay. FAU - Karnaukhov, Vadim AU - Karnaukhov V AD - Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia. AD - Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia. FAU - Paes, Wayne AU - Paes W AD - Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. FAU - Woodhouse, Isaac B AU - Woodhouse IB AD - Medical Research Council (MRC) Human Immunology Unit, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. AD - Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM) Centre for Computational Biology, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, United Kingdom. FAU - Partridge, Thomas AU - Partridge T AD - Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. FAU - Nicastri, Annalisa AU - Nicastri A AD - The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. FAU - Brackenridge, Simon AU - Brackenridge S AD - Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. FAU - Shcherbinin, Dmitrii AU - Shcherbinin D AD - Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia. AD - Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia. FAU - Chudakov, Dmitry M AU - Chudakov DM AD - Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia. AD - Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia. AD - Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia. FAU - Zvyagin, Ivan V AU - Zvyagin IV AD - Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia. AD - Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia. FAU - Ternette, Nicola AU - Ternette N AD - The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. FAU - Koohy, Hashem AU - Koohy H AD - Medical Research Council (MRC) Human Immunology Unit, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. AD - Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM) Centre for Computational Biology, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, United Kingdom. FAU - Borrow, Persephone AU - Borrow P AD - Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. FAU - Shugay, Mikhail AU - Shugay M AD - Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia. AD - Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia. LA - eng GR - MR/K012037/MRC_/Medical Research Council/United Kingdom GR - R01 AI118549/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 - 20221220 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (HLA-A Antigens) RN - 0 (HLA-B Antigens) RN - 0 (HLA-C Antigens) RN - 0 (Peptides) SB - IM MH - Humans MH - *Haplotypes MH - *HLA-A Antigens/genetics MH - *HLA-B Antigens/genetics MH - *HLA-C Antigens/genetics MH - Peptides PMC - PMC9808399 OTO - NOTNLM OT - HLA OT - gene ontologies and pathways OT - mass spectrometry OT - molecular function OT - protein COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/01/07 06:00 MHDA- 2023/01/10 06:00 PMCR- 2022/01/01 CRDT- 2023/01/06 02:28 PHST- 2022/10/11 00:00 [received] PHST- 2022/11/21 00:00 [accepted] PHST- 2023/01/06 02:28 [entrez] PHST- 2023/01/07 06:00 [pubmed] PHST- 2023/01/10 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.1067463 [doi] PST - epublish SO - Front Immunol. 2022 Dec 20;13:1067463. doi: 10.3389/fimmu.2022.1067463. eCollection 2022.