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

Christa E Osuna,S Munir Alam,Norman L Letvin,Elizabeth Ehlinger,Ana Maria Gonzalez,Kara Anasti,Amy Shi Hung,Hsun-Hsien Chang,Daniel C Douek

doi:10.1371/journal.ppat.1004069

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.

Highlights

Virus-specific CD8+ T cells contribute to the control of HIV and simian immunodeficiency virus (SIV) replication [1,2] and are an important component of a protective immunity
It is thought that those virus-specific CD8+ T cells that are present at the highest frequency are predominantly responsible for eliciting control of viral infections
We characterized the functional differences between the SIV-specific cells present at high versus low frequencies in rhesus monkeys infected with simian immunodeficiency virus (SIV)

Summary

Introduction

Virus-specific CD8+ T cells contribute to the control of HIV and SIV replication [1,2] and are an important component of a protective immunity. The determinants of immunodominance hierarchies have been explored in the past in efforts to enhance the magnitude of particular epitope-specific CD8+ T cell responses through vaccination [6,7]. Such investigations have primarily focused on determining the mechanisms underlying the establishment of immunodominance [8,9,10,11,12]; less is known about the resulting functional differences between dominant and subdominant epitope-specific CD8+ T cells. Numerous studies have reported that individuals with superior control of HIV replication and delayed disease progression have higher frequencies of polyfunctional CD8+ T cells and such cells are thought to be an important component of a protective immune response during HIV infection [14,15,16,17]. In order to do so, a better understanding of the factors that contribute to the polyfunctionality of a CD8+ T cell response is needed

Methods

Findings

Discussion

Conclusion