Daan Pieren

175 General discussion and future perspectives survival of KIR + RA + T cells by preventing overactivation. Remaining KIR + RA + T cells can actively suppress other T cells as the negative feedback through NKG2A has disappeared. Moreover, we speculate that the transcription factor Helios contributes to survival of KIR + RA + T cells as observed in murine CD8 + Tregs. As a side note, in contrast to our finding that the proportion of NKG2A + RA + T cells declines with age, a recent study by Pereira et al . reported an increase of NKG2A + cells within the highly differentiated CD27 - CD28 - CD8 + T-cell subset at older age [71]. Re-analysis of our data to match the analysis of Pereira et al . still indicated a decline of NKG2A + CD8 + T cells within the CD27 - CD28 - cell subset with age (data not shown). One possible explanation for these contrasting results may be the CMV status of the study participants. All donors we included in our study were seronegative for CMV to exclude bias towards CMV-induced changes to CD8 + T cells, such as induction of NKG2A expression by CD8 +  T cells [78]. CMV status was not reported in the study by Pereira et al . Figure 4. Molecular interactions of NKG2A + RA + and KIR + RA + T cells with their target T cell. Schematic representation of the hypothesized activation of NKG2A + RA + T cells and KIR + RA + T cells, proposed molecular interactions with their target T cell, and their hypothesized differentiation from NKG2A + RA + into KIR + RA + T cells during aging. In young individuals, the T-cell receptor (TCR) interacts with HLA-E on the target T cell, which leads to initiation of a suppressive response, potentially through killing. However, the NKG2A receptor may also interact with HLA-E, resulting in the inhibition of TCR activation and neutralization of the suppressive response. As a result, the target T cell survives. With age, expression of NKG2A is lost, whereas expression of KIR is gained. The absence of NKG2A allows full TCR signaling, resulting in suppression of the target cell, possibly by killing. Expression of inhibitory KIRs may interact with HLA-B or HLA-C on the target T cell, preventing overactivation of KIR + RA + T cells and thereby contributes to survival of this cell subset. Similarly, KIR + RA + T cells gain expression of the transcription factor Helios promoting survival. 6