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 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. © 2014 osuna et al.