International Immunology, Vol. 16, No. 3, pp. 385-393,
March 2004
© 2004 Japanese Society for Immunology
Augmentation of NK cell-mediated cytotoxicity to tumor cells by inhibitory NK cell receptor blockers
1 Laboratory of Molecular Medicine, Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba 277-8562, Japan 2 National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan
Correspondence to: N. Matsumoto, Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Bioscience Building 602, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan. E-mail: nmtasu{at}k.u-tokyo.ac.jp
Transmitting editor: K. Okumura
NK cells monitor expression of MHC class I by inhibitory receptors and preferentially kill cells that lose or down-regulate MHC class I expression. One possible mechanism by which tumor cells evade NK cell killing is continued expression of appropriate MHC class I ligands to engage inhibitory receptors on NK cells. We show here that small-mol.-wt blockers against the mouse inhibitory NK cell receptor Ly49A enhance NK cell killing of such tumor cells. We identified Ly49A-binding peptides by selecting phages with the capacity to bind recombinant Ly49A expressed in Escherichia coli from a phage display random peptide library. The Ly49A-binding peptides could also bind Ly49A expressed on mammalian cells. Importantly, the Ly49A-binding peptides blocked Ly49A recognition of its MHC class I ligands H-2Dd and H-2Dk. Moreover, blockade of Ly49A by the peptides enhanced cytotoxicity of Ly49A+ NK cells towards H-2Dd-expressing tumor cells. These results clearly indicate effectiveness of small-mol.-wt blockers of inhibitory NK cell receptors in enhancing NK cell-mediated killing of tumor cells that are otherwise resistant because of MHC class I expression.
Keywords: Ly49, MHC class I, mouse, peptide, phage display library
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