Regulatory dendritic cells activate NK cells towards an alternative phenotype through a mechanism involving IL-10, MHC-I, IL-18 and the activating receptor NKp46.

TORRES, NICOLÁS IGNACIO; SPALLANZANI, RAÚL GERMÁN; ZIBLAT, ANDREA; RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; ARAYA, ROMINA ELIZABETH; NÚÑEZ, SOL YANEL; SIERRA, JESSICA MARIEL; DOMAICA, CAROLINA INÉS; FUERTES, MERCEDES BEATRIZ; ZWIRNER, NORBERTO WALTER

Buenos Aires

Congreso; IV Latinamerican Society for Immunodeficiencies (LASID) Meeting, LXIII Meeting of the Argentinean Society of Immunology and II French-Argentinean Immunology Meeting.; 2015

Latinamerican Society for Immunodeficiencies (LASID) y Sociedad Argentina de Inmunología (SAI)

Background: The functional consequences of the interaction between dendritic cells(DC) and NK cells play an essential role during the immune responses againstvirus-infected cells and tumors. In addition, tumor microenvironment promotesthe expansion of regulatory dendritic cells (regDC), which may contribute toimmune escape. As little is known about the consequences of the crosstalkbetween regDC and NK cells, the aim of this work was to explore the outcome ofsuch crosstalk and to unravel the underlying mechanisms. Methods: 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. Results: NK cells co-cultured with regDC or mDC upregulated theactivation markers CD69 and CD25. However, NK cells co-cultured with regDC didnot up-regulate CD56 as NK cells co-cultured with mDC. Also, NK cellsco-cultured with regDC secreted lower amounts of IFN-g than NK cells exposed to mDC, an effect that was in part due to insufficientsecretion of IL-18, but not IL-12 or IL-15 and/or induction of NK cellapoptosis. Blocking experiments demonstrated that regDC curb IFN-g secretion by NK cells through a dominant suppressive mechanisminvolving IL-10, inhibitory receptors and unexpectedly, engagement of the activatingreceptor NKp46. Conclusions: Ourfindings identify an inhibitory role of regDC, and describe a novel inhibitoryfunction for NKp46 in the control of NK cell function.