CONICET | Buscador de Institutos y Recursos Humanos

Cross talk between mature dendritic cells (mDCs) and NK cells through the cell surfacereceptors NKp30 and DNAM-1 and the cytokines IL-12, IL-15, IL-18 and IFN-γ results in a reciprocalactivation of both cells. However, the outcome of the cross talk between tolerogenic DCs (tDCs)and NK cells, which may take place within a tumor microenvironment where tDCs are abundant,remains unknown. Previously, we observed that tDCs prevent IFN-γ secretion by NK cells in amechanism involving cell surface receptors and soluble factors. Thus, the objective of this studywas to elucidate the mechanisms underlying such NK cell effector function silencing promoted bytDCs. Human tDCs were generated from monocyte-derived DCs treated with LPS+dexamethasoneand indentified as CD1a+MHC-II+CD14-CD86low and IL-12lowIL-10high. Upon co-culture with NKcells for 24h, we observed that extensively washed tDCs (but not mDCs) prevented IFN-γ secretionby NK cells (202±88pg/ml vs. 1105±502pg/ml; p<0.001). Inhibition of IFN-γ secretion was not dueto DC-induced NK cell apoptosis, as total apoptosis of NK cells after co-culture with iDCs, mDCs ortDCs were -3.9±5.3%, 14.4±6.0% and 4.4±5.6%, respectively over basal levels (NK cells alone). Toinvestigate the receptors involved in this response, we performed blocking assays with anticytokineand anti-NK cell receptor mAbs. Blockade of IL-10 and, unexpectedly, blockade of theactivating receptor NKp46 (but not NKp30, NKp44 or NKG2D) restored the ability of NK cells tosecrete IFN-γ upon co-culture with tDCs (871,8±343,5pg/ml and 1072±427,1pg/ml vs.273,7±205,4pg/ml, respectively; p<0.05 in each case). Thus, tDCs preclude NK cell IFN-γ secretionthrough IL-10 production and promote a previously unrecognized inhibitory signal through NKp46.Our findings unravel a novel immunosuppressive mechanism of possible relevance within a tumormilieu and could be relevant as tolerogenic mechanism for NK cells to avoid self attack duringautoimmunity.