Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes

Jonathan A Trujillo; Stephanie Gras; Kelly-Anne Twist; Nathan P Croft; Rudragouda Channappanavar; Jamie Rossjohn; Anthony W Purcell; Stanley Perlman

doi:10.4049/jimmunol.1400111

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Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes

Journal article

Peer reviewed

Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes

Jonathan A Trujillo, Stephanie Gras, Kelly-Anne Twist, Nathan P Croft, Rudragouda Channappanavar, Jamie Rossjohn, Anthony W Purcell and Stanley Perlman

Journal of immunology (Baltimore, Md. : 1950), Vol.192(11), pp.5245-5256

06/01/2014

DOI: 10.4049/jimmunol.1400111

PMCID: PMC4052115

PMID: 24795457

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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.

CD8-Positive T-Lymphocytes - pathology

Humans

Peptides - immunology

Histocompatibility Antigens Class I - immunology

Peptides - genetics

Viral Proteins - immunology

Coronavirus Infections - genetics

Viral Proteins - genetics

Antigens, Viral - genetics

Epitopes, T-Lymphocyte - genetics

Histocompatibility Antigens Class I - genetics

Mutation, Missense

Coronavirus Infections - immunology

Coronavirus - immunology

Antigens, Viral - immunology

Animals

Coronavirus - genetics

Mice

Epitopes, T-Lymphocyte - immunology

HeLa Cells

CD8-Positive T-Lymphocytes - immunology

Amino Acid Substitution

Details

Title: Subtitle: Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes
Creators: Jonathan A Trujillo - Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242
Stephanie Gras - Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
Kelly-Anne Twist - Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
Nathan P Croft - Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
Rudragouda Channappanavar - Department of Microbiology, University of Iowa, Iowa City, IA 52242
Jamie Rossjohn - 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
Anthony W Purcell - Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
Stanley Perlman - 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
Resource Type: Journal article
Publication Details: Journal of immunology (Baltimore, Md. : 1950), Vol.192(11), pp.5245-5256
DOI: 10.4049/jimmunol.1400111
PMID: 24795457
PMCID: PMC4052115
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Grant note: F31 AI093129 / NIAID NIH HHS AI093129 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS R01 NS036592 / NINDS NIH HHS
Language: English
Date published: 06/01/2014
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9983777346502771

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