Sara van den Berg

122 Chapter 5 sustained in tonsillar lymphoid tissue where CMV-specific T-cells were less abundant than EBV-specific T-cells despite higher IL-7R α expression [70]. Figure 1. The advanced differentiation phenotype of CMV-specific CD8 T-cells. The advanced differentiated CMV-specific CD8 T-cell are typified by either expression or down-modulation of different surface receptors, cytokines and transcription factors. Surface receptors that are expressed are depicted in blue on the left side of the cell, whereas down-modulated or non-expressed surface receptors are depicted in gray on the right side of the cell. CMV-specific CD8 T-cells express the CD45 isoform CD45RA, different natural killer receptors (CD85j, CD56, CD57, NKG2A and KLRG1), IL-15R α and the homing receptors CX3CR1 and CD44. These cells do not express or lowly express CD45RO, costimulatory receptors CD27 and CD28, natural killer receptors (KIRs and NKG2C), inhibitory receptors (PD-1, TIM-3, CD160 and 2B4), homing receptors (CXCR6, CCR1, CD62L and CCR7) and cytokine receptors IL-2R β (CD122) and IL-7R α (CD127). CMV-specific CD8 T-cells have intermediate expression of the transcription factor Eomes and strong expression of transcription factors Hobit, Blimp-1 and T-bet. Related to this transcription profile is the high expression of cytokines IFN- γ and TNF- α and the cytotoxic molecules granzyme B (GrB) and perforin. In general, IL-2 production by CMV-specific CD8 T-cells is low. IS THE ADVANCED DIFFERENTIATED T-CELL PHENOTYPE UNIQUE? The above described advanced differentiated CD8 T-cell phenotype is clearly observed for CMV-specific T-cells, and could be considered as a distinct type of effector-memory (EM) T-cells. The phenotype involves expression of inhibitory molecules such as KLRG1, CD57