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Human cytomegalovirus (HCMV) infection is the most common cause of congenital viral infections and a major source of morbidity and mortality after organ transplantation. NK cells are pivotal effector cells in the innate defense against CMV. Recently, hallmarks of adaptive responses, such as memory-like features, have been recognized in NK cells. HCMV infection elicits the expansion of an NK cell subset carrying an activating receptor heterodimer, comprising CD94 and NKG2C (CD94/ NKG2C), a response that resembles the clonal expansion of adaptive immune cells. Here, we determined that expansion of this [NKG2C.sup.+] subset and general NK cell recovery rely on signals derived from [CD14.sup.+] monocytes. In a coculture system, a subset of [CD14.sup.+] cells with inflammatory monocyte features produced IL-12 in response to HCMV-infected fibroblasts, and neutralization of IL-12 in this model substantially reduced CD25 upregulation and [NKG2C.sup.+] subset expansion. Finally, blockade of CD94/NKG2C on NK cells or silencing of the cognate ligand HLA-E in infected fibroblasts greatly impaired expansion of [NKG2C.sup.+] NK cells. Together, our results reveal that IL-12, [CD14.sup.+] cells, and the CD94/NKG2C/HLA-E axis are critical for the expansion of [NKG2C.sup.+] NK cells in response to HCMV infection. Moreover, strategies targeting the [NKG2C.sup.+] NK cell subset have the potential to be exploited in NK cell-based intervention strategies against viral infections and cancer., Introduction NK cells are a critical part of the multilayered innate defense line against infectious agents and malignancies. Their control relies on the integration of multiple signals received via inhibitory [...]

Abstract: To exploit autologous NK cells for cancer immunotherapy, it is highly relevant to circumvent killer cell immunoglobulin‐like receptor (KIR)‐mediated self‐inhibition of human NK cells by HLA‐I–expressing tumor cells. Here, we show that stimulation of NK cells with IL‐12/15/18 for two days led to downregulation of surface expression of the inhibitory KIR2DL2/L3, KIR2DL1 and KIR3DL1 receptors on peripheral blood NK cells. Downregulation of KIR expression was attributed to decreased KIR mRNA levels which could be re‐induced already 3 days after re‐culture in IL‐2. Reduced KIR2DL2/L3 expression on IL‐12/15/18–activated NK cells resulted in less inhibition upon antibody‐mediated KIR engagement and increased CD16‐dependent cytotoxicity in redirected lysis assays. Most importantly, downregulated KIR2DL2/L3 expression enabled enhanced cytotoxicity of IL‐12/15/18–stimulated NK cells against tumor cells expressing cognate HLA‐I molecules. NK cells pre‐activated with IL‐12/15/18 were previously shown to exert potent anti‐tumor activity and memory‐like long‐lived functionality, mediating remission in a subset of acute myeloid leukemia (AML) patients in a clinical trial. Our study reveals a novel mechanism of IL‐12/15/18 in improving the cytotoxicity of NK cells by reducing their sensitivity to inhibition by self–HLA‐I due to decreased KIR expression, highlighting the potency of IL‐12/15/18–activated NK cells for anti‐tumor immunotherapy protocols. [ABSTRACT FROM AUTHOR]