Regulatory dendritic cells suppress NK cell activation by promoting IL-10 secretion and activating an NKp46-mediated inhibitory circuit

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

Honolulu

Congreso; ?Immunology 2013? (100th Congress of the American Association of Immunologists); 2013

The American Association of Immunologists

Regulatory dendritic cells (regDC) constrain the immune response in physiological and pathological conditions including tumor settings. Cross-talk between mature dendritic cells (mDC) and NK cells leads to reciprocal activation of both cells, but the impact of regDC on NK cells remains unknown. Our aim was to investigate the functional outcome and mechanisms underlying the interactions between regDC and NK cells. Human regDC generated from monocyte-derived DC treated with LPS and dexamethasone, opposed to mDC, triggered very little amounts of IFN-g secretion by NK cells. This effect was partially due to insufficient amounts of IL-18. Blocking experiments demonstrated that regDC have the potential ability to stimulate IFN-g secretion by NK cells through NKp30, but that this effect was overridden by a suppressive circuit that involves IL-10, NK cell inhibitory receptors and, unexpectedly, engagement of the activating receptor NKp46. Surprisingly, the opposing role of NKp30 and NKp46 on IFN-g secretion was also observed during the cross-talk between mDC and NK cells. Accordingly, similar amounts of NKp46 ligands were found to be expressed on mDC and regDC. Our findings unveil a previously unrecognized regulatory mechanism through which regDC regulate NK cell activation and identify a novel inhibitory role for NKp46 which counterbalances the stimulatory activity of NKp30. These results might be relevant in shutting-down NK cell-mediated anti-tumor immune responses.