Browsing School, Graduate by Subject "Killer Cells, Natural"
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Genetic and Functional Studies of the Evolutionarily Oldest Natural Killer Receptor, NKp30NKp30 is a Natural Cytotoxicity Receptor (NCR) expressed by Natural Killer (NK) cells and other lymphocytes. NKp30 is the only evolutionarily conserved NCR found in all jawed vertebrates and it coevolves with its ligand B7-H6. Using sharks as a model, we found NKp30 gene expression in subsets of mature and immature T cells, suggesting that T cells and NK cells share common features in these primitive vertebrates. To understand NKp30’s evolutionary origin, we examined genomic regions containing NKp30 and its homologs in vertebrates in different Classes. We observed that loci in paralogous regions containing NKp30 homologs are well conserved, suggesting the presence of NKp30 ancestors and other linked immune genes before the emergence of vertebrates 550 million years ago. Indeed, the corresponding region is also present in invertebrates. We hypothesize that this genomic region encompassed the “Primordial Immune Complex,” containing genes playing roles in immunity at the origin of vertebrates.
NK1.1+B220+ Cell Depletion Enhances the Rejection of Established Melanoma by TAA-Specific CD4+ T CellsFive-year survival rates for patients diagnosed with metastatic melanoma are less than 5%. Adoptive cell transfer (ACT) has achieved an objective response of 50% by Response Evaluation Criteria in Solid Tumors (RECIST) in this patient population. For ACT to be maximally effective, the host must first be lymphodepleted. It is hypothesized that lymphodepletion may remove regulatory elements and cytokine sinks, or increase the activation and availability of antigen presenting cells (APCs). We use an in vivo model to study the ACT of tumor-associated antigen (TAA)-specific CD4+ T cells (TRP-1 cells). We have discovered that depletion of NK1.1+ and B220+ cells enhances the rejection of established melanoma tumors by adoptively transferred TRP-1 cells. Our data suggest that the most likely cell population responsible for suppressing the activity of adoptively transferred TRP-1 cells is premature natural killer (pre-mNK) cells. NK1.1+ cell depletion increases the number of TRP-1 cells, the serum concentration of pro-inflammatory cytokines, and host survival after ACT. Our data suggest that NK1.1+ cells use an NKG2D- and programmed death-ligand 1 (PD-L1)- dependent mechanism to suppress the activity of adoptively transferred TRP-1 cells. We believe that future ACT therapy designs should include a regimen to encourage an anti-tumor rather than pro-tumor immune response from NK1.1+B220+ cells.
The Regulation of Natural Killer Cells through Prostaglandin E2 EP ReceptorsNatural Killer (NK) cell function is compromised by prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), but very little is known about the mechanism by which PGE<sub>2</sub> affects NK effector activity. Specifically, nothing is known regarding which PGE<sub>2</sub> receptor (EP1-4) mediates these effects. We have examined the role of individual EPs in regulating NK cells. Murine splenic or human NK cells express all four EP1-4 receptors. In endogenous NK cells from normal mice (N-NK), we show that activating all four NK-EP receptors with PGE<sub>2</sub> leads to less migration, reduced ability to lyse tumor targets, inhibited IFNγ secretion and decreased TNFα production. The ability of PGE<sub>2</sub> to inhibit N-NK cells is most likely through the EP4 receptor and, to a lesser degree, the EP2 receptor. Like PGE<sub>2</sub>, the EP4 agonist PGE1-OH blocked NK cell migration, inhibited cytotoxicity, and prevented cytokine secretion. The EP2 agonist, Butaprost, was able to inhibit cytotoxicity but did not blunt migration or effectively inhibit IFNγ secretion. In contrast to the inhibitory actions of PGE<sub>2</sub>, the EP1/EP3 agonist, Sulprostone, increased migration of N-NK cells. Thus, EP4 and EP1/3 may have opposing roles in regulating NK cells. NK cells from tumor bearing mice (T-NK) were compromised in many functions and showed reduced EP receptor expression. PGE<sub>2</sub> inhibits the potential of T-NK cells to migrate, exert cytotoxic effects, and secrete IFNγ. This ability of PGE<sub>2</sub> to inhibit NK cells from tumor bearing mice is mimicked by EP2 and EP4 agonists and, therefore most likely through EP2 and EP4 receptors. T-NK cells stimulated with PGE<sub>2</sub>, EP2 agonist (Butaprost), and EP4 agonist (PGE1-OH) were more sensitive to inhibition compared to N-NK cells. In contrast to the inhibitory effects of PGE<sub>2</sub> on cytotoxicity, and IFNγ production, TNFα secretion was actually induced in T-NK. Thus, PGE<sub>2</sub> inhibits TNFα secretion from N-NK, and further increases the constitutively high TNFα secretion from T-NK. Taken together our results show that tumor-derived PGE<sub>2</sub> is able to suppress many NK functions that are critical to tumor control and much of this inhibition is mediated through the EP4 receptor on NK cells. These data, combined with our published studies showing that tumor-expressed EP4 promotes metastasis, support the rationale to develop more effective EP antagonists as novel therapeutic agents.