Sara van den Berg

118 Chapter 5 INTRODUCTION Human cytomegalovirus (HCMV), a beta-herpesvirus family member, infects around 60% of the worldwide population [1]. In healthy individuals, HCMV establishes a persistent latent infection with episodes of reactivation. Although HCMV infection is usually asymptomatic, in immunocompromised (e.g. HCMV-seronegative recipients receiving organs of HCMV- positive donors) and immune immature individuals (neonates), HCMV can cause serious disease [2]. A remarkable feature of HCMV infection is the capacity to elicit large T-cell responses that do not follow the typical contraction pattern after primary infection. Instead, the percentages of CMV-specific T-cells remain high or even increase over time [3], a phenomenon named memory T-cell inflation [4, 5]. In the western world, frequencies around 10% of HCMV-specific T-cells of the total memory T-cell pool are commonly observed (with outliers >50%), and this is found in both healthy and immunocompromised individuals [6, 7]. In elderly, the frequency of circulating HCMV-specific T-cells is higher than in younger adults, and the reactivity of these cells can be restricted to a limited number of epitopes [8-11]. The increase in frequency of HCMV-specific CD8 T-cells with age is also observed in studies with immunocompromised individuals and is similar to frequencies found in healthy donors [12]. Besides the sustained large T-cell response, the phenotype of CMV-specific T-cells seems to be characteristic as well, typified by an advanced differentiation state. Here, we discuss the particulars of this “special” differentiation phenotype and asked the question whether the differentiation state of CMV-specific CD8 T-cells is unique. In addition, we discuss the potential impact of antigen exposure and aging on the differentiation status of CMV-specific CD8 T-cells. THE DIFFERENTIATION PHENOTYPE OF CMV-SPECIFIC CD8 T-CELLS CD45 isoforms Isoforms of the protein tyrosine phosphatase CD45 are expressed at various levels on hematopoietic cell lineages. The high molecular weight isoform CD45RA is expressed by naïve T-cells while the low molecular weight isoform CD45RO is expressed on activated and memory T-cells and is implicated in increasing the sensitivity of TCR signalling [13]. Advanced differentiation of T-cells is however characterized by a lack of CD45RO while CD45RA is re-expressed. A large proportion of the HCMV-specific T-cells have the latter phenotype (in combination with downregulation of costimulatory molecules also called TEMRA), and this seems quite unique for HCMV [14]. For example, Epstein-Barr virus (EBV)-specific CD8 T-cells are predominantly CD45RO positive [15] and human immunodeficiency virus (HIV)- specific T-cells express lower levels of CD45RA [16].