Regulatory Dendritic Cells Restrain NK Cell IFN-gamma Production through Mechanisms Involving NKp46, IL-10, and MHC Class I-Specific Inhibitory Receptors.

SPALLANZANI, RAÚL GERMÁN; TORRES, NICOLÁS IGNACIO; ÁVILA, DAMIÁN EZEQUIEL; ZIBLAT, ANDREA; RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; ROSSI, LUCAS EZEQUIEL; DOMAICA, CAROLINA INÉS; FUERTES, MERCEDES BEATRIZ; RABINOVICH, GABRIEL ADRIÁN; ZWIRNER, NORBERTO WALTER

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Lugar: Bethesda; Año: 2015 vol. 195 p. 2141 - 2148

0022-1767

Crosstalk between mature dendritic cells (mDC)and NK cells through the cell surface receptors NKp30 and DNAM-1 leads to theirreciprocal activation. However, the impact of regulatory dendritic cells(regDC) on NK cell function remains unknown. As regDC constrain the immuneresponse in different physiological and pathological conditions, the aim of thiswork was to investigate the functional outcome of the interaction between regDCand NK cells and the associated underlying mechanisms. RegDC generated frommonocyte-derived DC treated either with LPS and dexamethasone(DEX), vitamin D3 (VitD3) or VitD3 and DEX instructed NK cells to secrete lower amounts ofIFN-g than NK cells exposed to mDC. Although regDC triggered up-regulation of theactivation markers CD69 and CD25 on NK cells, they did not induceup-regulation of CD56 as mDC, and silenced IFN-g secretion throughmechanisms involving insufficient secretion of IL-18 but not IL-12 or IL-15 and/orinduction of NK cell apoptosis. Blocking experiments demonstrated that regDCcurb IFN-g secretion by NKcells through a dominant suppressive mechanism involving IL-10, NK cellinhibitory receptors and, unexpectedly, engagement of the activating receptorNKp46. Our findings unveil a previously unrecognized crosstalk through whichregDC shape NK cell function toward an alternative activated phenotype unableto secrete IFN-g, highlighting the plasticity of NK cells in response to tolerogenic stimuli. In addition, our findings contribute to identifya novel inhibitory role for NKp46 in the control of NK cell function, and havebroad implications in the resolution of inflammatory responses and evasion ofantitumor responses.