A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells.
NK cells provide a line of defense against tumors and virus-infected cells that have lost the expression of one or more MHC class I isoforms. Here, we investigate whether inhibitors of apoptosis can block the rejection of tumors mediated by NK cells, by introducing the long form of Fas-associated death domain-like IL-1beta-converting enzyme-associated inhibitory protein (FLIP(L)) and poxvirus cytokine response modifier A (CrmA) into the MHC class I-deficient T lymphoma cell line RMA-S. RMA-S cells do not normally express Fas in vitro, and it was previously postulated that the rejection of these tumors by NK cells is strictly perforin dependent. We show that perforin-deficient NK cells directly mediate Fas up-regulation on RMA-S cells and thereafter kill the cells in a Fas-dependent manner, and that RMA-S FLIP(L) and RMA-S CrmA are protected from such killing. When injected in immunocompetent recipients, RMA-S cells up-regulate Fas, rendering in vivo-passed mock-transduced cells sensitive to Fas-mediated apoptosis. Moreover, RMA-S FLIP(L) and RMA-S CrmA cells establish aggressive tumors, in contrast to RMA-S mock cells that are rejected. These results demonstrate that FLIP(L) and CrmA function as tumor progression factors by protecting MHC class I-deficient tumors from rejection mediated by NK cells. Moreover, our data indicate that death receptor-mediated apoptosis has a more prominent role in the clearance of NK-sensitive tumors than previously suggested.
Screpanti
V
V
Department of Immunology, Wenner-Gren Institute, University of Stockholm, Stockholm, Sweden. valli.screpanti@imun.su.se
Wallin
R P
RP
Ljunggren
H G
HG
Grandien
A
A
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018450:Disease Progression; D005822:Genetic Vectors / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011212:Poxviridae / Q000235:genetics; D015843:Serpins / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D015854:Up-Regulation / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics; D019014:fas Receptor / Q000096:biosynthesis
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D015853:Cysteine Proteinase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D015843:Serpins; D014764:Viral Proteins; D019014:fas Receptor; D054353:Perforin; C074641:interleukin-1beta-converting enzyme inhibitor