Bönnemann, Vivian2023-03-012023-03-012023http://hdl.handle.net/2003/4126610.17877/DE290R-23108Natural killer (NK) cells are innate immune cells that defend the human body against viral infections and tumor growth. NK cells exhibit two pathways to kill aberrant cells: the granule-mediated pathway and the death receptor-mediated pathway. Upon target cell contact, NK cells release granules that contain cytotoxic proteins such as granzymes. Although the main contributor granzyme B (GrzB) of the granule-mediated pathway has been investigated extensively, the role of the other four human granzymes A, H, K and M in NK cell cytotoxicity is less understood. In this thesis, we created fluorescent localization reporters to compare the activity of GrzB to the other four human granzymes within single target cells. The reporters not only visualize whether there is granzyme activity within the target cells, they also provide information about the kinetics. In this study, we observed that NK92 cells mainly kill their targets by using GrzB with partial support of GrzA. If GrzB is knocked out, GrzA acts as the only backup for GrzB and can induce apoptosis on its own. Although the granzymes H, K and M are expressed by all NK cells investigated in this study, they do not play a role for NK92 cytotoxicity, but rather in target cell killing by primary human NK cells. Here, we found different relevance of granzymes for resting (M > A > K > H) and activated (A > M > K > H) primary NK cells. In addition, CD56bright primary NK cells exhibit a higher GrzK content compared to CD56dim NK cells, but even though CD56bright NK cells also release higher levels of GrzK, target cells are still dominantly killed via GrzB. These results therefore further contribute to the understanding of the complexity of NK cell cytotoxicity.enNatural killer cellNK cellGranzymeCytotoxicityImmune system540doctoral thesisNK-ZelleCytotoxitätImmunsystem