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Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

Cellular & Molecular Immunology volume 7, pages 477–484 (2010)Cite this article

Abstract

Major histocompatibility complex (MHC) class I chain-related protein A (MICA), which is a ligand for human NKG2D, is expressed by a variety of epithelial tumor cells and promotes the activation of natural killer (NK), CD8+ and γδ-T cells. Although ectopic expression of MICA on tumor cells elicits anti-tumor responses, soluble MICA downregulates the activities of lymphocytes. In this study, we showed that recombinant, immobilized MICA (iMICA) molecules coated on plastic wells weakly promote peripheral NK cell activation, secretion of interferon (IFN)-γ and degranulation without inducing apoptosis. In addition, iMICA synergized with IL-15 and soluble 4-1BB ligand (s4-1BBL) to expand NK cells 25- to 42-fold in a 13-day culture, whereas NK cells stimulated only with IL-15 and s4-1BBL expanded 10- to 16-fold. In contrast to NK cells expanded by IL-15 and s4-1BBL stimulation, NK cells expanded long term in the presence of iMICA exhibited increased cytotoxicity against leukemia cells. These results suggest that large numbers of NK cells with high cytotoxicity can be generated by stimulation with IL-15 and s4-1BBL in the presence of iMICA and that these cells can be used for adoptive cancer immunotherapy.

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Acknowledgements

This work was supported by the National Natural Science Foundation (30400399 and 30671917), the Natural Science Fund of Jiangsu Province (BK2008215 and BK2004404) and the Natural Science Fund of the Educational Committee of Jiangsu Province (04KJB320162) in China.

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  1. WJ Gong, Department of Immunology, School of Medicine and Department of Gastroenterology, The Second Affiliated Hospital, Yangzhou University, Yangzhou 225001, China. E-mail: wjgong@yzu.edu.cn

Authors and Affiliations

  1. Department of Immunology, School of Medicine, Yangzhou University, Yangzhou, PR, China

    Weijuan Gong, Li Qian, Chunxiang Gong, Xianyuan Pan & Mingchun Ji

  2. Department of Gastroenterology, The Second Affiliated Hospital, Yangzhou University, Yangzhou, China

    Weijuan Gong & Weiming Xiao

  3. Testing Center, Yangzhou University, Yangzhou, China

    Maozhi Hu

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Gong, W., Xiao, W., Qian, L. et al. Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo. Cell Mol Immunol 7, 477–484 (2010). https://doi.org/10.1038/cmi.2010.41

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