The question what is the nature of the NKG2D-L involved was not addressed

in our study and has to be elucidated in future work. The data may be explained in the light of the two-step process of NK-cell activation. This model postulates that activation of resting NK cells requires engagement of at least two receptors that convey a priming and a triggering event 26. IL-2 and NCR have been defined as priming and triggering molecules, https://www.selleckchem.com/products/acalabrutinib.html respectively 26. Tumors may evade lysis through the lack of either efficient priming (type 1) or triggering (type 2). In our model, NK-cell activation correlated with MHC class I reduction of early-stage λ-myc lymphomas but not with their NKG2D-L levels (Fig. 3C, D), and in vitro lysis as well as tumor rejection not only required an activated NK-cell phenotype but were additionally dependent on NKG2D-L (Table 1, Fig. 4B). Since up-regulation of activation markers was mediated by MHC class Ilow target this website cells, by IL-15 or by DC, but not by NKG2D-L in the absence of the former stimuli, we suggest that NKG2D-L only act as a triggering signal, whereas MHC class Ilow cells provide a priming signal for NK cells. This was also suggested by our previous studies where we showed that in normal mice, transplanted MHC class I-positive lymphomas are effectively controlled provided (i) NK cells

are previously activated in vivo by injecting DC or CpG-ODN and (ii) sufficient amounts of NKG2D-L are expressed by the tumor 22. Transplanted MHC class Ilow lymphomas with sufficient NKG2D-L levels

are rejected even without preceding NK-cell activation 6. Whereas the priming signal provides unspecific activation, the tumor specificity of the NK-cell response may be mediated by the second signal. Taken together, apart from IL-2, other effectors that provide priming signals may include MHClow cells, DC, CpG-ODN or IL-15. Of course, it cannot be precluded that in λ-myc mice, other mechanisms may also act as priming signals and may be instrumental in inducing the activated phenotype of NK cells, for example microenvironment-derived cytokines. It is also possible that a higher fraction of immature NK cells is recruited to the tumor sites. The requirement of NKG2D-L Fludarabine ic50 for NK-cell triggering and tumor rejection also argues for its role in immune evasion. A synergism between “missing self” and NKG2D-mediated signals was also suggested by a previous in vitro study, but its implications for tumor surveillance in vivo and its significance in the context of the sequential NK-cell activation model were not addressed in this report 25. In transplantation models, injection of tumor cells with NK cell-activating potential gave rise to NK-cell cytotoxicity and IFN-γ expression and, eventually, to CTL responses 6, 43.