Inhibition of the death receptor pathway by cFLIP confers partial engraftment of MHC class I-deficient stem cells and reduces tumor clearance in perforin-deficient mice

NK cells mediate acute rejection of MHC class I-deficient bone marrow cell (BMC) grafts. However, the exact cytotoxic mechanisms of NK cells during ac ute BMC graft rejection are not well defined. Although the granule exocytos is pathway plays a major role in NK cell-mediated rejection, alternative pe rforin-independent mechanisms also exist. By analyzing the anti-apoptotic e ffects of cellular Fas-associated death domain-like IL-1-converting enzyme- inhibitory protein (cFLIP) overexpression, we investigated the possible rol e of death receptor-induced apoptosis in NK cell-mediated cytotoxicity. In the absence of perforin, we found that cFLIP overexpression reduces lysis o f tumor cells by NK cells in vitro and in vivo. In addition, perforin-defic ient NK cells were impaired in their ability to acutely reject cFLIP-overex pressing TAP-I knockout stem cells. These results emphasize the importance of NK cell death receptor-mediated killing during BMC grafts in the absence of perforin.