Similar results were obtained for mouse uterine NK cells, which also do not uniquely express CD9.18 eNK cells were shown to express perforin and although Jones et al.28 determined that eNK cells are cytotoxic (with the exception of early

proliferative phase eNK cells), their cytotoxic activity was extremely low (<20%). We have recently demonstrated that freshly isolated eNK cells exhibit extremely low levels of cytotoxicity and fail to produce cytokines such as IFN-γ, interferon-inducible protein-10 (IP-10), vascular endothelial growth factor (VEGF), and placenta growth factor (PLGF), without additional cytokine stimulation.20 This lack of NK function was observed in both proliferative and secretory phase eNK cells. Importantly, following activation with IL-15 (a cytokine that is important for NK cell differentiation,29,30 MG-132 price is known to be important Wnt inhibitor during pregnancy31,32 and whose receptor is expressed on eNK cells33) eNK cell cytotoxicity and their secretion of IFN-γ and IP-10 was up-regulated.20 Therefore, our results suggest that eNK cells are inert lymphocytes in the endometrium that are unable to kill target cells or to secrete NK known cytokines and growth factors, before IL-15 activation. Supporting these results, Eriksson et al.9 have also shown that eNK cells were able to produce IFN-γ

and IL-10 following activation with IL-12 and IL-15. Recently it was demonstrated that eNK clones are able to secrete VEGF-A and VEGF-C and thereby support the

endovascular process;34 however, these eNK cells were grown in culture in the presence of IL-2, a cytokine that was shown not to be expressed in the tissue and therefore is less suitable for in vitro activation of eNK cells.35 As stated above, we determined that freshly isolated eNK cells do not secrete VEGF and also do not contain VEGF transcripts.20 In the mouse uterus, decidualization and implantation of the blastocyst occur at gd 4. At gd 6, dNK can be detected in the decidua basalis, as they stain positive for DBA.19 From gd 8, dNK cells proliferate in the mesometrial lymphoid aggregate of pregnancy (MLAp), a transient lymphoid structure that forms between the two layers of myometrial Fenbendazole smooth muscle.36 In these lymphoid structures, dNK cells surround the uterine artery branches that enter the implantation sites. These cells peak in number at mid-gestation (gd 9–10) and their numbers decline afterwards, at gd 10–12.36 The receptor repertoire of mouse dNK cells has only recently been defined. Yadi et al.18 found that there are two distinct subsets of CD122+ CD3− dNK cells within the mouse uterus at mid-gestation. The smaller subset that was identified was similar in phenotype to peripheral blood mouse NK cells, expressing both NK1.1 and DX5. The second, larger subset displayed a unique phenotype: these dNK cells did not express the common markers of mature NK cells (NK1.1 and DX5) nor did they express the differentiation markers CD27 and CD43.