Daan Pieren

172 Chapter 6 cell killing similarly [59], indicating a potential killing mechanism of KIR + RA + T cells. Increased levels of CD107a is indicative of release of granules containing cytotoxic factors, such as granzymes and perforins [60,61], indicating that KIR + RA +  T cells may suppress through secretion of these factors ( Figure 3C ). Additionally, KIR + RA + T cells showed enrichment for the natural cytotoxicity triggering receptor 1 (NCR1/NKp46). NCR1 has been shown to promote expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [62], which can induce target-cell apoptosis upon binding to death receptor-5 (DR5) [63] ( Figure 3D ). Interestingly, activated CD4 + Tregs have been reported to express TRAIL and induce cell death through TRAIL-DR5 interaction [64]. Together, these findings indicate that the suppressive capacity of KIR + RA + T cells we describe in chapter 5 may possess several mechanisms that point towards target cell killing. It would be highly relevant for future research to address the potential target cell killing mechanisms that may result in suppression. Similarities between CD8 + Tregs , KIR + RA + T cells, and NKG2A + RA + T cells The existence and role of CD8 + Tregs in humans is controversial, as CD8 + T cells are mostly regarded a population of cells that are highly effective killer cells that target infected cells or tumor cells. In chapter 5 , we provide evidence for a subset of CD8 + Tregs in humans which we named KIR + RA + T cells. But how are KIR + RA + T cells triggered to exert suppression? And what is their relationship to NKG2A + RA + T cells? Interestingly, we found remarkable similarities between murine CD8 + Tregs and human KIR + RA +  T cells which may provide answers to this question ( Figure 4 ). Phenotypical and functional links between KIR + RA + T cells and CD8 + Tregs A subset of CD8 + Tregs identified in mice express receptors belonging to the Ly49 receptor family [65]. Ly49 receptors are the murine analogue of human KIRs, and both families are characterized by activating and inhibitory receptors [65,66]. In mice, 90% of the Ly49 + CD8 + Tregs express inhibitory Ly49F, which is thought to bind it’s ligand (possibly MHC I [67]) and prevent overactivation of these cells to ensure their survival [68]. These findings in mice may indicate that survival of KIR + RA + T cells humans may also be mediated by binding of KIR to MHC-I, more specifically by binding of KIR to HLA-B or HLA-C [69]. In chapter 5 , we assessed bulk KIR expression and we could therefore not further dissect differences in the expression of either activating or inhibitory KIRs, although the human variant of Ly49F, KIR3DL1, was present in our bulk analysis of KIRs. Possibly, isolating KIR + RA + T cells that express KIR3DL1 may specifically select