Daan Pieren

173 General discussion and future perspectives for regulatory KIR + RA + T cells. Additionally, strikingly similar to our findings on KIR + RA + T cells, murine CD8 + Ly49 + Tregs express CD122 and the transcription factor Helios [42,65]. Expression of Helios was shown to be vital for the survival and suppressive function of CD8 + Ly49 + Tregs, as deletion of Helios in these cells results in loss of suppression and in autoimmune disease [42]. Together, these findings indicate that Ly49 + CD8 + Tregs are the murine equivalent of human KIR + RA +  T cells and that expression of KIR and Helios may promote survival of KIR + RA + T cells ( Figure 4 ). Figure 3. Hypothetical suppression mechanisms of KIR + RA + T cells. Schematic representation of potential mechanisms for suppression of effector T cells by KIR + RA + T cells. ( A ) High expression of the co-inhibitory receptor TIGIT enables binding to its ligand CD155, resulting in two indirect suppressive mechanisms: first, enticing CD155- expressing dendritic cells (DCs) to convert to tolerogenic DCs that produce suppressive IL-10, and second, suppressing CD155-expressing effector T cells by secretion of IL-10 and FGL2. ( B ) High expression of CD122 indicates that KIR + RA + T cells are capable of scavenging IL-15 from the cellular microenvironment, thereby acting as an IL-15 sink and preventing activation and proliferation of effector T cells. ( C ) KIR + RA + T cells highly express degranulation marker CD107a after activation and the transcriptome of KIR + RA +  T cells is enriched for Granzyme H mRNA, indicating Granzyme-mediated killing of effector T cells. ( D ) Expression of NCR1 enhances expression of TRAIL, which enables binding of KIR + RA +  T cells to DR5 present on effector T cells, resulting in killing of the effector T cell. 6