Sara van den Berg

124 Chapter 5 T-cells exist directed against a distinct subset of epitopes, which never acquire the EM-like differentiation during the latent phase of infection [63]. In line with this are the observations that the enhanced differentiation state of the HCMV-specific T-cell is observed for different epitopes [32]. A critical aspect for virus-specific T-cells undergoing memory inflation or not, does not depend on the intrinsic property of the peptide epitope but on the context of viral gene expression. CMV epitopes that normally induce non-inflationary CD8 T-cell responses from its native site can induce an inflationary response due to C-terminal localization allowing better peptide processing, also leading to a more advanced differentiated phenotype [83, 84]. Besides the infectious dose, aging impacts also the differentiation status of the CMV-reactive T-cells. In cross-sectional studies it was observed that the number of HCMV-specific T-cells increases over time [6, 47]. And this is accompanied by an increase of HCMV-specific cells that re-express CD45RA [11] and express KLRG1 [47]. Moreover, by using new computational tools it was recently shown that inflationary MCMV-specific T-cells are progressively differentiating in time (based on the markers KLRG1, CD44, CD27 and CD62L), long after the initial infection [74, 85]. In line with these studies is the observation that telomeres of HCMV- specific CD8 T-cells are significantly shorter compared to the corresponding phenotypic subsets of the total CD8 T-cell pool [86]. The shortest telomere lengths were found in old individuals compared to young individuals in all different memory subsets (based on CD27 and CD45RA distinction). Overall, this indicates that with aging CMV-specific cells undergo more proliferation and enhanced differentiation. Important for the enhanced differentiation after CMV infection is the capacity of CMV to become latent. Essentially, latent genomes can sporadically desilence at certain genetic loci, which lead to gene expression of antigenic peptide-encoding genes without entering the productive cycle [87, 88] This allows intermittent re-exposure of antigen to the virus-specific T-cells, which keeps these cells “tickled” during a lifetime, but avoids continuous strong antigenic stimulation leading eventually to exhaustion as is the case for chronic infections with HIV or certain LCMV strains [89]. The large and gradual expansion of CMV-specific CD8 T-cells with an enhanced differentiation phenotype could be interpreted as a lack of complete control of the virus. The T-cells that show enhanced differentiation thus attempt to retain control over full reactivation of the virus. Accordingly, interference with an established MCMV infection by antiviral treatment reduces the frequency of the CMV-specific CD8 T-cell response, and also in this setting the CD8 T-cells reverted to a lesser differentiated phenotype compared to CMV-infected mice that are untreated [77]. It is generally assumed that the immune evasion strategies of CMV targeting the innate and adaptive immunity are critical for the long-term persistence of the virus [90, 91], but whether some of these strategies are capable of specifically modulating particular phenotypic characteristics of the CMV-specific T-cell is unknown. The need and purpose of the maintenance of high frequencies CMV specific CD8 T-cells that progressively differentiate is thus unclear and may be driven by an ongoing shift in the virus-host equilibrium.