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TCR Affinity Associated with Functional Differences between Dominant and Subdominant SIV Epitope-Specific CD8(+) T Cells in Mamu-A*01 (+) Rhesus Monkeys

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...

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Detalles Bibliográficos
Autores principales: Osuna, Christa E., Gonzalez, Ana Maria, Chang, Hsun-Hsien, Hung, Amy Shi, Ehlinger, Elizabeth, Anasti, Kara, Alam, S. Munir, Letvin, Norman L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990730/
https://www.ncbi.nlm.nih.gov/pubmed/24743648
http://dx.doi.org/10.1371/journal.ppat.1004069
Descripción
Sumario: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.