Sara van den Berg

120 Chapter 5 virus-specific memory T-cells [38], and this may be independent of their capacity to control viruses. Indeed, PD-1 expression is not associated with functional capacity (e.g. secretion of cytokines and degranulation). In addition, data showed that CD8 T-cells can further up- regulate PD-1 when they are activated [38]. Altogether this suggests that PD-1, expressed on CMV-specific T-cells, is independent from T-cell exhaustion. Natural killer receptors Although originally reported as natural killer cell receptors (NKRs), a number of these receptors such as immunoglobulin-like receptors (KIRs, LIRs such as CD85j) and lectin-like receptors (CD94/NKG2, KLRG1) are also expressed on CD8 T-cells [41]. These molecules are likely implicated in the fine-tuning of the anti-viral response. Indeed, primary CMV infection induces an increased expression of both inhibitory and activating NKRs, which remains high during the latent infection phase while viral load is undetectable [42]. Yet, the precise role of different NKRs remains to be determined. Similarity between CMV-specific T-cells and other chronic viruses is found in the expression patterns for several inhibiting NKRs. CMV-specific T-cells, just like EBV- and HIV-specific T-cells, show substantial expression of CD85j (ILT2/LIR-1) compared to the overall T-cell pool [43-45]. This CD85j expression is most abundant in TEMRAs and CD28 - CD8 T-cells [44], suggesting an advanced differentiation phenotype. In addition, the overwhelming majority of CMV, EBV and HIV-specific T-cells express KLRG1, often together with loss of expression of CD28 and CCR7, indicating that these cells have undergone multiple cell divisions but are still active in cytokine production [46, 47]. Also, expression of NKG2A is increased on CMV-specific CD8 T-cells [42, 48]. However, KIRs do not seem upregulated on CMV-specific T-cells and/or HIV-specific T-cells: only small fractions express CD158 variants or NKB-1 (KIR3DL1) [43, 49]. Although increased expression of NKG2C on CD8 T-cells is associated with CMV-seropositivity [42] and CMV-reactive T-cells upon restimulation show NKG2C expression [44], CMV-specific T-cells stained with MHC class I tetramers do not seem to express NKG2C [42, 50]. Overall, CD8 T-cells specific for CMV show low expression of KIRs and NKG2C and increased expression of CD85j, NKG2A and KLRG1 during the latent phase of the infection. CMV-specific CD8 T-cells also express the NKRs CD56 and CD57. CD56 + CD8 T-cells are known for their natural-killer like cytotoxity [51], and CD56 is shown on CMV-specific T-cells in renal transplant patients [52] and healthy individuals (unpublished observations, S. van den Berg and D. van Baarle). CD57 expression represents a cellular phenotype associated with poor proliferative capacity but high cytotoxic potential [53]. On CMV-specific T-cells, CD57 expression, often co-expressed with CD85j, increases with age, but a large variation in expression exist [44, 54]. CD57 expression on CMV, EBV, and HIV-specific CD8T-cells was low to moderate in adults [32, 46], whereas others reported overall a high expression on these virus-specific T-cells of CD57 in older subjects [55]. In the latter, CMV-specific T-cells seem to express CD57 at higher levels than EBV and HIV-specific T-cells, albeit not substantially.