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The role of antigen expression in shaping the repertoire of HLA presented ligands.

ABSTRACT: Human leukocyte antigen (HLA) presentation of peptides is a prerequisite of T cell immune activation. The understanding of the rules defining this event has large implications for our knowledge of basic immunology and for the rational design of immuno-therapeutics and vaccines. Historically, most of the available prediction methods have been solely focused on the information related to antigen processing and presentation. Recent work has, however, demonstrated that method performance can be boosted by integrating information related to antigen abundance. Here we expand on these later findings and develop an extended version of NetMHCpan, called NetMHCpanExp, integrating information on antigen abundance from RNA-Seq experiments. In line with earlier works, the model demonstrates improved performance for both HLA ligand and cancer neoantigen epitope prediction. Optimal results are obtained by use of sample-specific abundance information but also reference datasets can be applied with a limited performance drop. The developed tool is available at https://services.healthtech.dtu.dk/service.php?NetMHCpanExp-1.0.

SUBMITTER: Garcia Alvarez HM

PROVIDER: S-EPMC9437844 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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The role of antigen expression in shaping the repertoire of HLA presented ligands.

Garcia Alvarez Heli M HM Koşaloğlu-Yalçın Zeynep Z Peters Bjoern B Nielsen Morten M

iScience 20220817 9

Human leukocyte antigen (HLA) presentation of peptides is a prerequisite of T cell immune activation. The understanding of the rules defining this event has large implications for our knowledge of basic immunology and for the rational design of immuno-therapeutics and vaccines. Historically, most of the available prediction methods have been solely focused on the information related to antigen processing and presentation. Recent work has, however, demonstrated that method performance can be boos ...[more]

PMID: 36060059

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Project description:Recent clinical developments in antitumor immunotherapy involving T-cell related therapeutics have led to a renewed interest for human leukocyte antigen class I (HLA-I) binding peptides, given their potential use as peptide vaccines. Databases of HLA-I binding peptides hold therefore information on therapeutic targets essential for understanding immunity. In this work, we use in depth and accurate HLA-I peptidomics datasets determined by mass-spectrometry (MS) and analyze properties of the HLA-I binding peptides with structure-based computational approaches. HLA-I binding peptides are studied grouping all alleles together or in allotype-specific contexts. We capitalize on the increasing number of structurally determined proteins to (1) map the 3D structure of HLA-I binding peptides into the source proteins for analyzing their secondary structure and solvent accessibility in the protein context, and (2) search for potential differences between these properties in HLA-I binding peptides and in a reference dataset of HLA-I motif-like peptides. This is performed by an in-house developed heuristic search that considers peptides across all the human proteome and converges to a collection of peptides that exhibit exactly the same motif as the HLA-I peptides. Our results, based on 9-mers matched to protein 3D structures, clearly show enriched sampling for HLA-I presentation of helical fragments in the source proteins. This enrichment is significant, as compared to 9-mer HLA-I motif-like peptides, and is not entirely explained by the helical propensity of the preferred residues in the HLA-I motifs. We give possible hypothesis for the secondary structure biases observed in HLA-I peptides. This contribution is of potential interest for researchers working in the field of antigen presentation and proteolysis. This knowledge refines the understanding of the rules governing antigen presentation and could be added to the parameters of the current peptide-MHC class I binding predictors to increase their antigen predictive ability.

Dataset Information

The role of antigen expression in shaping the repertoire of HLA presented ligands.

Publications

The role of antigen expression in shaping the repertoire of HLA presented ligands.

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