in shielding and limiting the cytotoxic function of NK cells against stem cells in order to raise maximally the secretion of key cytokines for speedy and optimal differentiation of stem cells during inflammation. This is precisely what is observed in cancer patients in whom global decrease in NK, cytotoxic T cells and monocytes have all been reported [29]. In addition, the increase in IFN-c secretion by NK cells should provide the initial steps in increasing antigen specific functions of T and B cells and initiation of adaptive immunity. We have recently observed an NFkB independent rescue of oral epithelial cells by monocytes (manuscript in prep). Therefore, it is likely that monocytes elevate survival of MSCs and DPSCs through NFkB dependent and independent pathways. In addition, both the total population of monocytes and those depleted of CD16+ subsets were able to increase NFkB and survival of oral epithelial cells (manuscript in prep) and MSCs resulting in an increase in cytokine secretion. We have previously reported that rescue from cell death is governed by inverse induction of NFkB and JNK and decreased secretion of IgFbp6 in epithelial cells [26,30]. [31]. Whether monocytes prevent stem cell death through similar mechanisms should await future investigation. Our previous work demonstrated the decoupling of NK cell cytotoxicity from cytokine secretion [16]. The cytotoxic function of non-dissociated NK-tumor cell conjugates remained very low and did not increase when supplemented with IL-2 although they proliferated and secreted higher amounts of TNF-a and IFN-c in the supernatants [16]. In contrast, NK cells dissociated from the target conjugates exhibited more cytotoxic activity, but they proliferated poorly and secreted lower levels of TNF-a or IFN-c following IL-2 treatment. More importantly, a fraction of NK cells in non-dissociated NK-tumor conjugates were programmed for cell death by apoptosis [16]. Furthermore, the addition of intact and F(ab)’2 fragment of anti-CD16 antibodies in combination with IL-2 significantly and reproducibly inhibited the cytotoxic function of NK cells, but the NK cells secreted relatively higher amounts of IFN-c [18,19,20]. As mentioned above, we observed a similar References 1. Fibbe WE, Nauta AJ, Roelofs H (2007) Modulation of immune responses by mesenchymal stem cells. Ann N Y Acad Sci 1106: 272–278. 2. Nauta AJ, Fibbe WE (2007) Immunomodulatory properties of mesenchymal stromal cells. Blood 110: 3499–3506. 3. Nasef A, Ashammakhi N, Fouillard L (2008) Immunomodulatory effect of mesenchymal stromal cells: possible mechanisms. 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This function of anti-CD16 receptor antibody and monocytes therefore can be exploited to decrease rejection of stem cells by the NK cells. Indeed, for optimal engraftment of stem cells one may require to target both cytotoxic NK and T cells and in this regard the use of the combination of anti-CD16 antibody and OKT3 antibody should theoretically achieve this objective. We are currently using this strategy to improve engraftment of stem cells in pulp tissues. Given the high sensitivity of stem cells to NK cell cytotoxicity, it is possible that significant elevation in NK cell signaling by MSCs and subsequent initiation of signaling for anergy and cell death of a subset of NK cells contribute to the observed suppression of NK cell cytotoxicity. Indeed, significant down modulation of NK cell receptors NKp30, NKp44 and NKG2D was also observed after interaction of NK cells with MSCs [6]. 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(2006) Inhibition of nuclear factor kappa B (NFkappaB) activity in oral tumor cells prevents depletion of NK cells and increases their functional activation. Cancer Immunol Immunother 55: 1052–1063. PLoS ONE | www.plosone.org 13 March 2010 | Volume 5 | Issue 3 | e9874