Daan Pieren

171 General discussion and future perspectives [47]. Thus, these reports suggest that KIR + RA + T cells may interact with dendritic cells and other T cells to indirectly suppress the immune response ( Figure 3A ). The IL-15 receptor We show that KIR + RA + T cells express high levels of CD122, the β -chain of the IL-2 and IL-15 receptors. In mice, it has been shown that virtual memory T cells are highly responsive against IL-15 and require IL-15 for their development [38,53], which indicates that KIR + RA + T cells may interact with IL-15 more efficiently compared to other T cells. The response of virtual memory cells to IL-2 is still unclear and still remains to be addressed. Similar to virtual memory cells, CD8 + Tregs in mice were reported to be dependent on IL-15 for their development and suppressive function [54], indicating that the capacity to suppress may depend on IL-15 signaling. CD4 +  Tregs can suppress immune responses by acting as a ‘sink’ for IL-2 [55]. Hypothetically, high expression of CD122 may indicate that KIR + RA + T cells act as an IL-15 ‘sink’: extracting IL-15 that is present in the cellular microenvironment, thereby scavenging the IL-15 out of the system so that it can’t be used by other T cells ( Figure 3B ). Absence of IL-15 during influenza A virus infection in IL-15 knockout mice reduced deadly lung pathology inflicted by effector CD8 + T-cell responses [56], which may indicate that KIR + RA + T cells act as regulators that may limit lung pathology by indirectly suppressing T effector cells through scavenging of IL-15. Whereas we observed that a higher activation status of KIR + RA + T cells positively correlated with prolonged disease, it may be that the IL-15 levels exceeded the ‘sink capacity’ of KIR + RA + T cells allowing effector T cells to kill infected lung cells leading to prolonged presence of symptoms. Measuring the impact of IL-15 in vitro on KIR + RA + T-cell responses as well as measuring the level of IL-15 present in older adults suffering from viral respiratory infection may provide further insight into this process. Killing of other CD8 + T cells Suppression of T-cell responses through killing of T cells is one of the mechanisms that has been reported for CD4 + Tregs [57,58]. In these reports, CD4 + Tregs targeted activated CD4 + T cells, CD8 + T cells, monocytes, and dendritic cells, causing cell death of these target cells mediated by Granzyme B or perforin in a contact-dependent manner. Although we did not find Granzyme B or perforin to be enriched in KIR + RA + T cells in an unstimulated state, we found increased transcripts for Granzyme H. Moreover, we found highly increased levels of the degranulation marker CD107a in KIR + RA +  T cells after in vitro stimulation. Granzyme H is closely related to Granzyme B and can cause target- 6