Split anergized Natural Killer cells halt inflammation by inducing stem cell differentiation, resistance to NK cell cytotoxicity and prevention of cytokine and chemokine secretion
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Han-Ching Tseng1, Nicholas Cacalano2,3, Anahid Jewett1,3
1Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA
2Department of Radiation Oncology, Division of Molecular and Cellular Oncology UCLA School of Medicine, Los Angeles, CA, USA
3The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
Anahid Jewett, e-mail: [email protected]
Keywords: IFN-γ, NK, OSCSCs, cytotoxicity, regulatory NK
Received: November 14, 2014 Accepted: January 28, 2015 Published: March 27, 2015
The mechanism of suppression of NK cytotoxicity in cancer patients is not clearly established. In this paper we provide evidence that anergized NK cells induce differentiation of healthy Dental Pulp Stem Cells (DPSCs) or transformed Oral Squamous Cancer Stem Cells (OSCSCs) resulting in cell growth inhibition, resistance to NK cell-mediated cytotoxicity and prevention of inflammatory mediators secretion. Induction of cytotoxicity resistance in differentiated cells correlated with increased CD54 and MHC class I surface expression and mediated by the combination of IFN-γ and TNF-α since antibodies to both, but not each cytokine alone, was able to inhibit resistance. In contrast, inhibition of cytokine and chemokine release was mediated by IFN-γ since the addition of anti-IFN-γ antibody, and not anti-TNF-α, restored secretion of inflammatory mediators in NK cell cultures with differentiated DPSCs and OSCSCs. There was a gradual and time dependent decrease in MHC class I and CD54 expression which correlated with the restoration of NK cell cytotoxicity, augmentation of cytokine secretion and increased cell growth from days 0–12 post NK removal. Continuous presence of NK cells is required for the maintenance of cell differentiation since the removal of NK cell-mediated function reverses the phenotype and function of differentiated cells to their stem-like cells.
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