Crosstalk with regulatory dendritic cells promotes NK cell activation towards an alternative phenotype characterized by low secretion of IFN-gamma

TORRES NI; SPALLANZANI RG; ZIBLAT, ANDREA; RAFFO IRAOLAGOITIA, XIMENA L.; ARAYA RE; NUÑEZ, SOL Y.; SIERRA, JESSICA M.; SECCHIARI F; DOMAICA CI; FUERTES, MERCEDES BEATRIZ; ZWIRNER NW

Congreso; International Congress of Immunology; 2016

The functional consequences of the interaction between dendritic cells (DC) and NK cells play an essential role during the immune responses against virus-infected cells and tumors. In addition, tumor microenvironment promotes the expansion of regulatory dendritic cells (regDC), which may contribute to immune escape. As little is known about the consequences of the crosstalk between regDC and NK cells, the aim of this work was to explore the outcome of such crosstalk and to unravel the underlying mechanisms. Human NK cells and monocytes were isolated from blood. Monocytes were cultured for 6 d with GM-CSF and IL-4 to obtain immature DC (iDC). Then, iDC were stimulated with LPS to obtain mature DC (mDC) or LPS and dexamethasone, vitamin D3 or their combination to obtain regDC. NK cells co-cultured with regDC or mDC upregulated the activation markers CD69 and CD25. However, NK cells co- cultured with regDC did not up-regulate CD56 as NK cells co-cultured with mDC. Also, NK cells co-cultured with regDC secreted lower amounts of IFN-γ than NK cells exposed to mDC, an effect that was in part due to insufficient secretion of IL-18, but not IL-12 or IL-15 and/or induction of NK cell apoptosis. Blocking experiments demonstrated that regDC curb IFN-γ secretion by NK cells through a dominant suppressive mechanism involving IL-10, inhibitory receptors and unexpectedly, engagement of the activating receptor NKp46. Our findings identify an inhibitory role of regDC, and describe a novel inhibitory function for NKp46 in the control of NK cell function.