These results suggest that a primary function of the activating NK receptors in immune regulation is to control NK-cell production of immunomodulatory factors [76]. The human KIRs, which recognize HLA class I molecules as ligands, are functional homologs to the Ly49 receptors in mice [75]. KIR2DL4 is the human homolog of Ly49D in mice, therefore the genetic changes observed in KIR-activated human NK cells and Ly49D-activated mouse NK cells are mostly the same [75]. KIR2DL4 (CD158d) resides in endosomes within NK cells and binds to its soluble ligand, HLA-G, which is produced by fetal trophoblast cells during early pregnancy [66]. KIR2DL4 is an unusual member

of the polymorphic KIR family because Talazoparib research buy it possesses an NK-cell-activating function despite harboring an inhibitory

ITIM [77]. Microarray analysis of human NK cells undergoing sustained activation after treatment with a soluble anti-KIR2DL4 agonist mAb revealed upregulated genes typical of a senescent signature (such as Il6, Il8, IL1B, and p21), and the supernatants from KIR2DL4-activated NK cells could increase vascular permeability and promote angiogenesis [66]. GSI-IX concentration Thus, sustained activation of NK cells induces senescence in response to soluble HLA-G in the microenvironment, and may contribute to remodeling the maternal vasculature in early pregnancy [66]. An independent study using a human cytokine array to evaluate mRNA expression of 114 common human Mannose-binding protein-associated serine protease cytokine genes also showed that activation of human dNK cells by anti-KIR2DL4 mAb or HLA-G homodimer upregulates proinflammatory cytokines including IFN-γ, IL-6, IL-8, and TNF-α as well as proangiogenic protein vascular endothelial growth factor, which are essential for a successful pregnancy [77]. Malaria infection has been shown to trigger early activation and expansion of NK cells [78]. Microarray analysis of early blood responses in mice infected with erythrocytic-stage Plasmodium chabaudi revealed

that NK-cell-associated transcripts (such as lectin-like killer cell receptors, Prf1 and GzmA) in the blood increase dramatically, which was confirmed by the observations of increased NK-cell numbers and frequency in both the blood and spleen 72 h after infection [79]. At the molecular level within these P. chabaudi infection induced pNK cells, subsequent microarray analysis revealed a cell proliferation signature consistent with the above findings [79]. NK cells are essential for controlling certain viral infections in the host. Murine cytomegalovirus (MCMV) infection induces NK-cell activation and expansion, and thus serves as an ideal model for physiological NK-cell activation [41, 80, 81]. Bezman et al.