Cutting edge: tumor rejection mediated by NKG2D receptor-ligand interaction is dependent upon perforin

Y Hayakawa, JM Kelly, JA Westwood… - The Journal of …, 2002 - journals.aai.org
Y Hayakawa, JM Kelly, JA Westwood, PK Darcy, A Diefenbach, D Raulet, MJ Smyth
The Journal of Immunology, 2002journals.aai.org
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) β. Rae-1β expression on class I-deficient RMA-S lymphoma cells enhanced primary
NK cell-mediated tumor rejection in vivo, whereas RMA-Rae-1β tumor cells were rejected by
a combination of NK cells and CD8+ T cells. Rae-1β expression stimulated NK cell
cytotoxicity and IFN-γ secretion in vitro, but not proliferation. Surprisingly, only NK cell …
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) β. Rae-1β expression on class I-deficient RMA-S lymphoma cells enhanced primary NK cell-mediated tumor rejection in vivo, whereas RMA-Rae-1β tumor cells were rejected by a combination of NK cells and CD8+ T cells. Rae-1β expression stimulated NK cell cytotoxicity and IFN-γ secretion in vitro, but not proliferation. Surprisingly, only NK cell perforin-mediated cytotoxicity, but not production of IFN-γ, was critical for the rejection of Rae-1β-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.
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