Prevention of Cytotoxic T Cell Escape Using a Heteroclitic Subdominant Viral T Cell Determinant

PLoS Pathogens

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