A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells

J Immunol. 2001 Aug 15;167(4):2068-73. doi: 10.4049/jimmunol.167.4.2068.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytotoxicity, Immunologic / genetics
  • Disease Progression
  • Genetic Vectors / immunology
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • Graft Rejection / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Killer Cells, Natural / immunology*
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / immunology
  • Lymphoma, T-Cell / pathology
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Transplantation
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Poxviridae / genetics
  • Serpins / genetics
  • Serpins / physiology*
  • Tumor Cells, Cultured / immunology
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / transplantation
  • Up-Regulation / immunology
  • Viral Proteins / genetics
  • fas Receptor / biosynthesis


  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Cflar protein, mouse
  • Cysteine Proteinase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Serpins
  • Viral Proteins
  • fas Receptor
  • Perforin
  • interleukin-1beta-converting enzyme inhibitor