Sara van den Berg

125 5 Hallmarks of CMV-specific T-cells Another important aspect might be the broad tropism of CMV and its systemic spread as localized CMV infection results in lesser inflation and less advanced differentiation [92, 93]. The distinctive tropism of CMV, including the wide variety of targeT-cells, innate immune cells such as myeloid cells as CMV vehicles, and the infrequent expression of immediate early genes leading to abortive reactivation, may thus co-determine the fate of the T-cell response, and such characteristics may be the key differences compared to other chronic viruses that frequently reactivate, like EBV. Finally, the size of the genome of CMV is relatively large (compared to most other viruses), which may contribute to elicit larger T-cell responses and to the likelihood to encompass epitopes inducing inflationary T-cell responses. CONCLUDING REMARKS The characteristics of CMV-specific T-cells, i.e. maintenance of high numbers and the late differentiated EM-like phenotype, has been a subject of interest. Although the CMV-specific memory T-cell populations are diverse (in magnitude and phenotype) between individuals, it is evident that a large proportion of these cells are advanced differentiated. This particular phenotype seems to be related to the nature of CMV infection because it is more abundantly found upon CMV infection compared to other chronic viruses. The CMV-specific T-cells are often late-stage differentiated T-cells, have shorter telomeres and express inhibitory molecules such as KLRG1, CD57 and CD85j, yet the cells are nevertheless functional with respect to cytokine production and cytotoxicity [94]. Further studies are needed to unravel this seemingly conflicting feature of CMV-specific T-cells. Large prospective studies in humans could provide further insight, but such studies may still be complicated given the possible impact of MHC heterogeneity in the human population compared to inbred mice [95]. Notably, the data discussed here reflects mainly the differentiation of the circulating CMV-specific T-cells, which represents a subgroup of the total CD8 T-cell pool in the body. Whether a late-differentiated phenotype “uniquely” related to CMV infection is also present in the tissue-resident memory T-cell population remains to be elucidated. Several papers reveal a dual impact of CMV infection and aging on immune subsets [96-100]. Prevalence of CMV infection increases with age [101, 102], suggesting that CMV may take advantage over a senescent immune system. How long term infection of CMV is able to change the virus- host balance leading to gradual higher levels of advanced differentiated T-cells is unknown. Due to aging, immune control may gradually wane leading to more frequent reactivation.