Prevention of cytotoxic T cell escape using a heteroclitic subdominant viral T cell determinant

Noah S Butler; Alex Theodossis; Andrew I Webb; Roza Nastovska; Sri Harsha Ramarathinam; Michelle A Dunstone; Jamie Rossjohn; Anthony W Purcell; Stanley Perlman

doi:10.1371/journal.ppat.1000186

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Prevention of cytotoxic T cell escape using a heteroclitic subdominant viral T cell determinant

Journal article

Open access

Peer reviewed

Prevention of cytotoxic T cell escape using a heteroclitic subdominant viral T cell determinant

Noah S Butler, Alex Theodossis, Andrew I Webb, Roza Nastovska, Sri Harsha Ramarathinam, Michelle A Dunstone, Jamie Rossjohn, Anthony W Purcell and Stanley Perlman

PLoS pathogens, Vol.4(10), pp.e1000186-e1000186

10/2008

DOI: 10.1371/journal.ppat.1000186

PMCID: PMC2563037

PMID: 18949029

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Abstract

High affinity antigen-specific T cells play a critical role during protective immune responses. Epitope enhancement can elicit more potent T cell responses and can subsequently lead to a stronger memory pool; however, the molecular basis of such enhancement is unclear. We used the consensus peptide-binding motif for the Major Histocompatibility Complex molecule H-2K(b) to design a heteroclitic version of the mouse hepatitis virus-specific subdominant S598 determinant. We demonstrate that a single amino acid substitution at a secondary anchor residue (Q to Y at position 3) increased the stability of the engineered determinant in complex with H-2K(b). The structural basis for this enhanced stability was associated with local alterations in the pMHC conformation as a result of the Q to Y substitution. Recombinant viruses encoding this engineered determinant primed CTL responses that also reacted to the wildtype epitope with significantly higher functional avidity, and protected against selection of virus mutated at a second CTL determinant and consequent disease progression in persistently infected mice. Collectively, our findings provide a basis for the enhanced immunogenicity of an engineered determinant that will serve as a template for guiding the development of heteroclitic T cell determinants with applications in prevention of CTL escape in chronic viral infections as well as in tumor immunity.

Thermodynamics

Coronavirus Infections - prevention & control

T-Lymphocytes, Cytotoxic - immunology

Temperature

Mutagenesis, Site-Directed

Immunodominant Epitopes - chemistry

Models, Molecular

Antigen Presentation - genetics

Epitopes, T-Lymphocyte - genetics

Antigen Presentation - immunology

Coronavirus Infections - immunology

Antigenic Modulation - genetics

T-Lymphocytes, Cytotoxic - physiology

Epitopes, T-Lymphocyte - chemistry

Murine hepatitis virus - immunology

H-2 Antigens - immunology

Animals

H-2 Antigens - genetics

H-2 Antigens - chemistry

Models, Biological

Mice

Immunodominant Epitopes - genetics

Protein Stability

Murine hepatitis virus - genetics

Details

Title: Subtitle: Prevention of cytotoxic T cell escape using a heteroclitic subdominant viral T cell determinant
Creators: Noah S Butler - Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America
Alex Theodossis
Andrew I Webb
Roza Nastovska
Sri Harsha Ramarathinam
Michelle A Dunstone
Jamie Rossjohn
Anthony W Purcell
Stanley Perlman
Resource Type: Journal article
Publication Details: PLoS pathogens, Vol.4(10), pp.e1000186-e1000186
DOI: 10.1371/journal.ppat.1000186
PMID: 18949029
PMCID: PMC2563037
NLM abbreviation: PLoS Pathog
ISSN: 1553-7366
eISSN: 1553-7374
Publisher: United States
Grant note: T32 AI007511 / NIAID NIH HHS\r\nR01 NS036592 / NINDS NIH HHS
Language: English
Date published: 10/2008
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9983777475702771

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