Abstract
CD8+ T-cell responses against latent viruses can cover considerable portions of the CD8+ T-cell compartment for many decades, yet their initiation and maintenance remains poorly characterized in humans. A key question is whether the clonal repertoire that is raised during the initial antiviral response can be maintained over these long periods. To investigate this we combined next-generation sequencing of the T-cell receptor repertoire with tetramer-sorting to identify, quantify and longitudinally follow virus-specific clones within the CD8+ T-cell compartment. Using this approach we studied primary infections of human cytomegalovirus (hCMV) and Epstein Barr virus (EBV) in renal transplant recipients. For both viruses we found that nearly all virus-specific CD8+ T-cell clones that appeared during the early phase of infection were maintained at high frequencies during the 5-year follow-up and hardly any new anti-viral clones appeared. Both in transplant recipients and in healthy carriers the clones specific for these latent viruses were highly dominant within the CD8+ T-cell receptor Vβ repertoire. These findings suggest that the initial antiviral response in humans is maintained in a stable fashion without signs of contraction or changes of the clonal repertoire.
Highlights
The selection and maintenance of CD8+ T-cell clones is pivotal in antiviral immune responses
Animal models of persisting infections exist (e.g. LCMV, murine CMV (mCMV)), these models can usually only be studied over a period of weeks to months, while in humans latent infections need to be controlled for many decades
We used a new technology that allowed us to track virus specific immune cells (CD8+ T cells) over time in a quantitative manner. When we used this technology to study the evolution of latent responses against herpesviruses we found that immune responses were very rigid and did not evolve over time
Summary
The selection and maintenance of CD8+ T-cell clones is pivotal in antiviral immune responses. Most of our current understanding of this process is based on animal models of infection that allow tight control over many factors such as viral titers and the exact time of infection [1,2,3]. These models are invaluable for our understanding of immune recognition and regulation, there are limitations in translating their findings to the human situation. A particular example is the CD8+ T-cell maintenance in persisting (or latent) viral infections (e.g. HIV, human cytomegalovirus (hCMV), and Epstein-Barr Virus (EBV)). For hCMV it has been reported that the phenotype of virus-specific CD8+ T-cells changes over time from activated T cell (CD8+CD45R0+CD27+HLA-DR+) in the early phase to resting vigilant effector-type cell (CD8+CD45RA+CCR72CD272CD282)
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