NKp46- and IL-10-dependent silencing of NK cell-mediated IFN-gamma production upon cross talk with tolerogenic dendritic cells

ÁVILA, DAMIÁN EZEQUIEL; ROSSI, LUCAS EZEQUIEL; DOMAICA, CAROLINA INÉS; SPALLANZANI, RAÚL GERMÁN; ZIBLAT, ANDREA; RABINOVICH, GABRIEL ADRIÁN; ZWIRNER, NORBERTO WALTER

Buenos Aires

Congreso; 1º Congreso Franco-Argentino de Inmunología y 58a Reunión Anual de la Sociedad Argentina de Inmunología; 2010

Sociedad Argentina de Inmunología y Sociedad Francesa de Inmunología

Cross talk between mature dendritic cells (mDCs) and NK cells through the cell surface receptors NKp30 and DNAM-1 and the cytokines IL-12, IL-15, IL-18 and IFN-γ results in a reciprocal activation 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 a mechanism involving cell surface receptors and soluble factors. Thus, the objective of this study was to elucidate the mechanisms underlying such NK cell effector function silencing promoted by tDCs. Human tDCs were generated from monocyte-derived DCs treated with LPS+dexamethasone and indentified as CD1a+MHC-II+CD14-CD86low and IL-12lowIL-10high. Upon co-culture with NK cells for 24h, we observed that extensively washed tDCs (but not mDCs) prevented IFN-γ secretion by NK cells (202±88pg/ml vs. 1105±502pg/ml; p<0.001). Inhibition of IFN-γ secretion was not due to DC-induced NK cell apoptosis, as total apoptosis of NK cells after co-culture with iDCs, mDCs or tDCs were -3.9±5.3%, 14.4±6.0% and 4.4±5.6%, respectively over basal levels (NK cells alone). To investigate the receptors involved in this response, we performed blocking assays with anti-cytokine and anti-NK cell receptor mAbs. Blockade of IL-10 and, unexpectedly, blockade of the activating receptor NKp46 (but not NKp30, NKp44 or NKG2D) restored the ability of NK cells to secrete 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 secretion through IL-10 production and promote a previously unrecognized inhibitory signal through NKp46. Our findings unravel a novel immunosuppressive mechanism of possible relevance within a tumor milieu and could be relevant as tolerogenic mechanism for NK cells to avoid self attack during autoimmunity.