title: Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes.
abstract: Peptides that bind poorly to MHC class I molecules often elicit low-functional avidity T cell responses. Peptide modification by altering the anchor residue facilitates increased binding affinity and may elicit T cells with increased functional avidity toward the native epitope ("heteroclitic"). This augmented MHC binding is likely to increase the half-life and surface density of the heteroclitic complex, but precisely how this enhanced T cell response occurs in vivo is not known. Furthermore, the ideal heteroclitic epitope will elicit T cell responses that completely cross-react with the native epitope, maximizing protection and minimizing undesirable off-target effects. Such epitopes have been difficult to identify. In this study, using mice infected with a murine coronavirus that encodes epitopes that elicit high (S510, CSLWNGPHL)- and low (S598, RCQIFANI)-functional avidity responses, we show that increased expression of peptide S598 but not S510 generated T cells with enhanced functional avidity. Thus, immune responses can be augmented toward T cell epitopes with low functional avidity by increasing Ag density. We also identified a heteroclitic epitope (RCVIFANI) that elicited a T cell response with nearly complete cross-reactivity with native epitope and demonstrated increased MHC/peptide abundance compared with native S598. Structural and thermal melt analyses indicated that the Q600V substitution enhanced stability of the peptide/MHC complex without greatly altering the antigenic surface, resulting in highly cross-reactive T cell responses. Our data highlight that increased peptide/MHC complex display contributes to heteroclitic epitope efficacy and describe parameters for maximizing immune responses that cross-react with the native epitope.
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242;
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Trujillo
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Kelly-Anne
authors.initials: KA
authors.lastname: Twist
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Croft
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242;
authors.forename: Rudragouda
authors.initials: R
authors.lastname: Channappanavar
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; and Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; Department of Microbiology, University of Iowa, Iowa City, IA 52242; stanley-perlman@uiowa.edu.
authors.forename: Stanley
authors.initials: S
authors.lastname: Perlman
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D017934:Coronavirus / Q000235:genetics / Q000276:immunology*; D018352:Coronavirus Infections / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D014764:Viral Proteins