PLoS Pathogens | |
Prevention of Cytotoxic T Cell Escape Using a Heteroclitic Subdominant Viral T Cell Determinant | |
Roza Nastovska1  Michelle A. Dunstone1  Stanley Perlman1  Sri Harsha Ramarathinam1  Noah S. Butler2  Alex Theodossis3  Anthony W. Purcell4  Jamie Rossjohn4  Andrew I. Webb4  | |
[1] Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia;Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America;Immunology Graduate Program, University of Iowa, Iowa City, Iowa, United States of America;The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia | |
关键词: T cells; Cytotoxic T cells; Antigens; Microbial mutation; Immune response; Major histocompatibility complex; Cell staining; Viral replication; | |
DOI : 10.1371/journal.ppat.1000186 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
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-2Kb 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-2Kb. 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.
【 授权许可】
CC BY
【 预 览 】
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RO201902017875790ZK.pdf | 608KB | download |