Sara van den Berg

121 5 Hallmarks of CMV-specific T-cells Adhesion molecules and lymphocyte homing CMV-specific CD8 T-cells are largely negative for CCR7 and CD62L [16, 17, 49], which are homing receptors for lymphoid organs. This property, which is shared with T-cells specific for other chronic viruses, allows the cells to circulate throughout the body, and reside in peripheral tissue, spleen and blood. CX3CR1, which recognizes fractalkine expressed by endothelial cells, is abundantly expressed by CMV-specific cells [10, 56] during the primary and latent infection, whereas CCR1 and CXCR6 are only present during the acute phase [37]. High and intermediate expression of CX3CR1 seems to be unique for CMV specific CD8 T-cells in both human and mice [37, 56], as the frequency of this chemokine receptor on EBV [57], HBV and HCV-specific T-cells is much lower [58]. CMV-specific CD8 T-cells with intermediate expression of CX3CR1 associates with self-renewal potential, but the role of CX3CR1 seems to be redundant since memory T-cell inflation is unaltered in case of CX3CR1 deficiency [56]. In addition, CXCR3 is commonly expressed on CMV-specific T-cells as well as EBV-specific T-cells [57]. The homing cell adhesion molecule CD44 is uniformly high expressed on all CMV-specific T-cells [48, 59]. Transcription factors, cytokines and cytotoxic molecules Transcription factors (TFs) are crucial regulators of cellular differentiation and function including the cytotoxic potential and cytokine secretion. For CD8 T-cells, the TFs Eomes and T-bet are particularly useful to determine the functional profile. For example, T-bet dim and Eomes high expression profiles are associated with expression of exhaustion markers as observed in HIV-specific T-cells, whereas many CMV and EBV-specific T-cells exhibit intermediate levels of Eomes and high levels of T-bet [37, 40, 60]. Blimp-1 and the Homolog of Blimp-1 in T-cells (Hobit) are also clearly expressed by CMV-specific CD8 T-cells [61, 62]. Related to the above described TF profile is the high granzyme B and perforin expression in CMV-specific CD8 T-cells [39, 40, 49, 63]. These cells also abundantly produce IFN- γ and TNF after re-stimulation, while IL-2 is produced by only a subset of the inflationary CMV-specific CD8 T-cells [63]. The expression of the above described effector molecules is consistent with the functional non-exhaustion phenotype of CMV-specific T-cells, and underline their functional status and requirement for lifelong protection against viral dissemination [64]. Analysis of transcriptional networks in inflating cells reveals a module of genes strongly driven by T-bet, not seen in T-cell exhaustion [65]. The low IL-2 production may coincide with the reduced expression of IL-2R β (CD122/IL- 15R β ) on CMV-specific CD8 T-cells [37, 48, 63, 66]. In addition, virus-specific effector CD8 T-cells activated in vivo during primary EBV or CMV infection down-regulate IL-7R α (CD127) and IL-15R α (CD215) expression [67]. With time, CMV-specific CD8 T-cells maintain high level of IL-15R α . This contrasts with the lower expression of IL7R α on CMV-specific CD8+ T-cells compared to EBV-specific CD8 T-cells [32, 68-70]. Interestingly, IL-7R α expression was tightly associated with population size in blood [70]. However, this correlation was not