title: TCR contact residue hydrophobicity is a hallmark of immunogenic CD8+ T cell epitopes.
abstract: Despite the availability of major histocompatibility complex (MHC)-binding peptide prediction algorithms, the development of T-cell vaccines against pathogen and tumor antigens remains challenged by inefficient identification of immunogenic epitopes. CD8(+) T cells must distinguish immunogenic epitopes from nonimmunogenic self peptides to respond effectively against an antigen without endangering the viability of the host. Because this discrimination is fundamental to our understanding of immune recognition and critical for rational vaccine design, we interrogated the biochemical properties of 9,888 MHC class I peptides. We identified a strong bias toward hydrophobic amino acids at T-cell receptor contact residues within immunogenic epitopes of MHC allomorphs, which permitted us to develop and train a hydrophobicity-based artificial neural network (ANN-Hydro) to predict immunogenic epitopes. The immunogenicity model was validated in a blinded in vivo overlapping epitope discovery study of 364 peptides from three HIV-1 Gag protein variants. Applying the ANN-Hydro model on existing peptide-MHC algorithms consistently reduced the number of candidate peptides across multiple antigens and may provide a correlate with immunodominance. Hydrophobicity of TCR contact residues is a hallmark of immunogenic epitopes and marks a step toward eliminating the need for empirical epitope testing for vaccine development.
authors.affiliation: Simon A. Levin Mathematical, Computational, and Modeling Sciences Center, Center for Personalized Diagnostics, and.
authors.forename: Diego
authors.initials: D
authors.lastname: Chowell
authors.affiliation: Center for Personalized Diagnostics, and School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85287;
authors.forename: Sri
authors.initials: S
authors.lastname: Krishna
authors.affiliation: Department of Immunobiology, King's College London, London SE1 9RT, United Kingdom;
authors.forename: Pablo D
authors.identifier: http://orcid.org/0000-0003-1980-1230
authors.initials: PD
authors.lastname: Becker
authors.affiliation: Department of Immunobiology, King's College London, London SE1 9RT, United Kingdom;
authors.forename: Clément
authors.initials: C
authors.lastname: Cocita
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98195; and.
authors.forename: Jack
authors.initials: J
authors.lastname: Shu
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98195; and.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98195; and.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
authors.affiliation: Department of Immunobiology, King's College London, London SE1 9RT, United Kingdom; linda.klavinskis@kcl.ac.uk Joseph.Blattman@asu.edu Karen.Anderson.1@asu.edu.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Klavinskis
authors.affiliation: Center for Infectious Diseases and Vaccinology, Arizona State University, Tempe, AZ 85287 linda.klavinskis@kcl.ac.uk Joseph.Blattman@asu.edu Karen.Anderson.1@asu.edu.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Blattman
authors.affiliation: Center for Personalized Diagnostics, and linda.klavinskis@kcl.ac.uk Joseph.Blattman@asu.edu Karen.Anderson.1@asu.edu.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D011336:Probability; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry
chemical_list: D000596:Amino Acids; D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell; D054301:gag Gene Products, Human Immunodeficiency Virus
keywords: MHC class I; T cell; epitope prediction; immunogenicity; nonself; vaccine
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