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 acute BMC graft rejection are not well defined. Although the granule exocytosis pathway plays a major role in NK cell-mediated rejection, alternative perforin-independent mechanisms also exist. By analyzing the anti-apoptotic effects of cellular Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein (cFLIP) overexpression, we investigated the possible role of death receptor-induced apoptosis in NK cell-mediated cytotoxicity. In the absence of perforin, we found that cFLIP overexpression reduces lysis of tumor cells by NK cells in vitro and in vivo. In addition, perforin-deficient NK cells were impaired in their ability to acutely reject cFLIP-overexpressing TAP-1 knockout stem cells. These results emphasize the importance of NK cell death receptor-mediated killing during BMC grafts in the absence of perforin.
Taylor
M A
MA
Graduate Program in Immunology, and Departments of Pathology, and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. mesha.taylor@utsouthwestern.edu
Chaudhary
P M
PM
Klem
J
J
Kumar
V
V
Schatzle
J D
JD
Bennett
M
M
D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation / Q000276:immunology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis*; D005805:Genes, MHC Class I / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D007694:Killer Cells, Natural; D008562:Membrane Glycoproteins / Q000172:deficiency*; D051379:Mice; D008817:Mice, Mutant Strains; D009368:Neoplasm Transplantation / Q000276:immunology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014181:Transplantation Immunology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor; D054353:Perforin