title: Dual functions of natural killer cells in selection and differentiation of stem cells; role in regulation of inflammation and regeneration of tissues.
abstract: Accumulated evidence from our laboratory indicates that conditioned or anergized NK cells have the ability to induce resistance of healthy stem cells and transformed cancer stem cells through both secreted factors and direct cell-cell contact by inducing differentiation. Cytotoxic function of NK cells is suppressed in the tumor microenvironment by a number of distinct effectors and their secreted factors. Furthermore, decreased peripheral blood NK cell function has been documented in many cancer patients. We have previously shown that NK cells mediate significant cytotoxicity against primary oral squamous carcinoma stem cells (OSCSCs) as compared to their more differentiated oral squamous carcinoma cells (OSCCs). In addition, human embryonic stem cells (hESCs), human mesenchymal stem cells (hMSCs), human dental pulp stem cells (hDPSCs) and induced human pluripotent stem cells (hiPSCs) were all significantly more susceptible to NK cell mediated cytotoxicity than their differentiated counterparts or parental cells from which they were derived. We have also reported that inhibition of differentiation or reversion of cells to a less-differentiated phenotype by blocking NFκB or gene deletion of COX2 significantly augmented NK cell function. Furthermore, the induction of resistance of the stem cells to NK cell mediated cytotoxicity and their subsequent differentiation is amplified when either the stem cells or the NK cells were cultured in the presence of monocytes. Therefore, we propose that the two stages of NK cell maturation namely CD16+CD56dimCD69- NK cells are important for the lysis of stem cells or poorly differentiated cells whereas the CD16dim/-CD56dim/+CD69+NK cells are important for differentiation and eventual regeneration of the tissues and the resolution of inflammation, thus functionally serving as regulatory NK cells (NK(reg)). CD16 receptor on the NK cells were found to be the receptor with significant potential to induce NK cell anergy, however, our recent data indicated that NKp46 but not NKp30 or NKp44 were also able to induce significant anergy in NK cells, although the levels were less when compared to CD16 receptor triggering. The concept of split anergy in NK cells and generation of NK(reg) and its contribution to cell differentiation, tissue repair and regeneration and in tumor resistance will be discussed in this review.
authors: 1. The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, and Division of Oral Biology and Medicine, UCLA School of Dentistry, University of California, Los Angeles, CA 90095;
authors: Anahid
authors: A
authors: Jewett
authors: Yan-Gao
authors: YG
authors: Man
authors: Han-Ching
authors: HC
authors: Tseng
keywords: NFκB; NK; Regulation.; apoptosis; cancer stem cells; differentiation
references: Oncol Rep. 2004 Aug;12(2):339-45
references: 15254699
references: J Immunol. 1997 Nov 15;159(10):4815-22
references: 9366406
references: J Immunol. 1995 Jan 15;154(2):491-9
references: 7814862
references: Clin Immunol. 2000 Jul;96(1):19-28
references: 10873424
references: Transpl Immunol. 2008 Apr;19(1):1-11
references: 18346631
references: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2307-12
references: 9482881
references: Cancer Res. 1993 Dec 1;53(23):5610-2
references: 8242612
references: Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):1994-2003
references: 16609008
references: Prog Exp Tumor Res. 1970;13:1-27
references: 4921480
references: PLoS One. 2010 Mar 31;5(3):e9874
references: 20360990
references: Cancer Res. 1999 Jul 15;59(14):3299-303
references: 10416581
references: J Lipid Mediat Cell Signal. 1994 Feb;9(1):19-25
references: 8032712
references: Hum Immunol. 2003 May;64(5):505-20
references: 12691701
references: Int Immunopharmacol. 2011 Jul;11(7):802-7
references: 21237299
references: Nat Immunol. 2002 Nov;3(11):991-8
references: 12407406
references: Clin Cancer Res. 1999 Feb;5(2):329-34
references: 10037182
references: Nat Immun. 1993 Jul-Oct;12(4-5):194-208
references: 8257826
references: Oncogene. 2002 Dec 5;21(55):8404-13
references: 12466961
references: J Biol Chem. 2008 Apr 18;283(16):10958-66
references: 18292095
references: Semin Immunopathol. 2009 Sep;31(3):333-43
references: 19639317
references: Transplant Rev. 1971;7:3-25
references: 5146537
references: Oncogene. 2002 Apr 4;21(15):2334-46
references: 11948417
references: Blood Cells Mol Dis. 2008 Jan-Feb;40(1):94-100
references: 17827037
references: J Am Acad Dermatol. 2002 Aug;47(2):169-87; quiz 188-90
references: 12140463
references: Ann Surg Oncol. 1996 Mar;3(2):176-84
references: 8646519
references: Cytokine. 1995 May;7(4):372-9
references: 8589268
references: Cancer Res. 1988 Dec 15;48(24 Pt 1):6992-8
references: 3263897
references: Blood. 2008 Feb 1;111(3):1327-33
references: 17951526
references: Exp Cell Res. 2011 Apr 1;317(6):849-58
references: 21255568
references: Biochim Biophys Acta. 2009 Aug;1796(1):11-8
references: 19269310
references: Cancer Immunol Immunother. 2008 Jul;57(7):1053-66
references: 18188563
references: J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Nov 1;10(3):331-40
references: 7552495
references: Immunity. 2004 Aug;21(2):137-48
references: 15308095
references: Biochem Biophys Res Commun. 2007 Aug 31;360(3):553-9
references: 17618600
references: Proc Natl Acad Sci U S A. 1999 May 11;96(10):5640-4
references: 10318937
references: Trends Immunol. 2001 Nov;22(11):633-40
references: 11698225
references: J Clin Immunol. 1995 Jan;15(1):35-44
references: 7759599
references: J Exp Med. 1995 Jan 1;181(1):339-44
references: 7528771
references: Gut. 1997 Jan;40(1):113-9
references: 9155587
references: Biochem Biophys Res Commun. 2007 Sep 28;361(3):586-92
references: 17673180
references: Cell Immunol. 1995 Jan;160(1):91-7
references: 7842490
references: Blood. 2005 Feb 15;105(4):1815-22
references: 15494428
references: Clin Cancer Res. 1996 Jan;2(1):161-73
references: 9816103
references: PLoS One. 2010 Jul 16;5(7):e11590
references: 20661281
references: J Invest Dermatol. 2004 Jul;123(1):101-8
references: 15191549
references: Zhonghua Yi Xue Za Zhi. 1997 Mar;77(3):167-70
references: 9596951
references: Isr J Med Sci. 1971 Jan;7(1):9-16
references: 4101103
references: Cancer Immunol Immunother. 2006 Sep;55(9):1052-63
references: 16328384
references: Nat Med. 1996 Dec;2(12):1367-70
references: 8946837
references: Nature. 2002 Jun 20;417(6891):861-6
references: 12075355
references: J Immunol. 1996 Feb 1;156(3):907-15
references: 8558016
references: Cancer Chemother Pharmacol. 2005 Jul;56(1):22-8
references: 15791453
references: Int J Hematol. 2011 Mar;93(3):294-300
references: 21374075
references: Stem Cells. 2008 Jan;26(1):212-22
references: 17932417
references: J Immunol. 1998 Jun 1;160(11):5669-75
references: 9605174
references: Gynecol Oncol. 2005 Dec;99(3):704-13
references: 16126266
references: J Clin Immunol. 1996 Jan;16(1):46-54
references: 8926285
references: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2796-801
references: 21825174
references: Gynecol Oncol. 1997 Jun;65(3):391-8
references: 9190963
references: J Dent Res. 2006 Dec;85(12):1061-73
references: 17122156
references: Nat Med. 2004 Jan;10(1):48-54
references: 14702634
references: Curr Opin Immunol. 2010 Apr;22(2):231-7
references: 20144856
references: Cell Immunol. 1994 Apr 1;154(1):273-86
references: 7907529
references: Blood Rev. 2006 May;20(3):123-37
references: 16364519
references: J Immunol. 1997 Sep 15;159(6):3057-67
references: 9300731
references: Immunol Cell Biol. 2011 Feb;89(2):216-24
references: 20567250