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PLoS Pathog. 2014 Apr 17;10(4):e1004069. doi: 10.1371/journal.ppat.1004069. eCollection 2014 Apr.

TCR affinity associated with functional differences between dominant and subdominant SIV epitope-specific CD8+ T cells in Mamu-A*01+ rhesus monkeys.

Author information

1
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
2
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
3
Children's Hospital Informatics Program, Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, United States of America.
4
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America.
5
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America; Department of Pathology, Duke University of Medicine, Durham, North Carolina, United States of America.

Abstract

Many of the factors that contribute to CD8+ T cell immunodominance hierarchies during viral infection are known. However, the functional differences that exist between dominant and subdominant epitope-specific CD8+ T cells remain poorly understood. In this study, we characterized the phenotypic and functional differences between dominant and subdominant simian immunodeficiency virus (SIV) epitope-specific CD8+ T cells restricted by the major histocompatibility complex (MHC) class I allele Mamu-A*01 during acute and chronic SIV infection. Whole genome expression analyses during acute infection revealed that dominant SIV epitope-specific CD8+ T cells had a gene expression profile consistent with greater maturity and higher cytotoxic potential than subdominant epitope-specific CD8+ T cells. Flow-cytometric measurements of protein expression and anti-viral functionality during chronic infection confirmed these phenotypic and functional differences. Expression analyses of exhaustion-associated genes indicated that LAG-3 and CTLA-4 were more highly expressed in the dominant epitope-specific cells during acute SIV infection. Interestingly, only LAG-3 expression remained high during chronic infection in dominant epitope-specific cells. We also explored the binding interaction between peptide:MHC (pMHC) complexes and their cognate TCRs to determine their role in the establishment of immunodominance hierarchies. We found that epitope dominance was associated with higher TCR:pMHC affinity. These studies demonstrate that significant functional differences exist between dominant and subdominant epitope-specific CD8+ T cells within MHC-restricted immunodominance hierarchies and suggest that TCR:pMHC affinity may play an important role in determining the frequency and functionality of these cell populations. These findings advance our understanding of the regulation of T cell immunodominance and will aid HIV vaccine design.

PMID:
24743648
PMCID:
PMC3990730
DOI:
10.1371/journal.ppat.1004069
[Indexed for MEDLINE]
Free PMC Article
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