Abstract
We have investigated the primary immunity generated in vivo by MHC class I-deficient and -competent tumor cell lines that expressed the NKG2D ligand retinoic acid early inducible-1 (Rae-1) beta. Rae-1beta expression on class I-deficient RMA-S lymphoma cells enhanced primary NK cell-mediated tumor rejection in vivo, whereas RMA-Rae-1beta tumor cells were rejected by a combination of NK cells and CD8(+) T cells. Rae-1beta expression stimulated NK cell cytotoxicity and IFN-gamma secretion in vitro, but not proliferation. Surprisingly, only NK cell perforin-mediated cytotoxicity, but not production of IFN-gamma, was critical for the rejection of Rae-1beta-expressing tumor cells in vivo. This distinct requirement for perforin activity contrasts with the NK cell-mediated rejection of MHC class I-deficient RMA-S tumor cells expressing other activating ligands such as CD70 and CD80. Thus, these results indicated that NKG2D acted as a natural cytotoxicity receptor to stimulate perforin-mediated elimination of ligand-expressing tumor cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Death / genetics
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Cell Death / immunology
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Cells, Cultured
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Cytotoxicity, Immunologic / genetics
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Graft Rejection / genetics
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Graft Rejection / immunology*
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Interferon-gamma / metabolism
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Ligands
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Lymphocyte Activation / genetics
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Lymphoma, T-Cell / immunology
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Lymphoma, T-Cell / metabolism
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Lymphoma, T-Cell / pathology
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Membrane Proteins / biosynthesis
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Membrane Proteins / metabolism
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Membrane Proteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NK Cell Lectin-Like Receptor Subfamily K
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Perforin
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Pore Forming Cytotoxic Proteins
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Receptors, Immunologic / metabolism
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Receptors, Immunologic / physiology*
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Receptors, Natural Killer Cell
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Tretinoin / physiology
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Tumor Cells, Cultured / immunology
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Tumor Cells, Cultured / metabolism
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Tumor Cells, Cultured / pathology
Substances
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Klrk1 protein, mouse
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Ligands
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Membrane Glycoproteins
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Membrane Proteins
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NK Cell Lectin-Like Receptor Subfamily K
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Pore Forming Cytotoxic Proteins
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Raet1a protein, mouse
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Raet1b protein, mouse
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Receptors, Immunologic
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Receptors, Natural Killer Cell
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Perforin
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Tretinoin
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Interferon-gamma