Human M2 macrophages limit NK cell effector functions through secretion of 2 TGF-beta and engagement of CD85j

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

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Lugar: Bethesda; Año: 2018 vol. 200 p. 1008 - 1015

0022-1767

NK cells play important roles during immunosurveillance against tumors and viruses as they trigger cytotoxicity against susceptible cells and secrete pro-inflammatory cytokines such as IFN-g. In addition, upon activation, macrophages can become pro-inflammatory (M1) or anti-inflammatory (M2) cells. Although the consequences of the crosstalk between M1 and NK cells are known, the outcome of the crosstalk between M2 and NK cells remains ill-defined. Therefore, in the current work, we investigated the outcome and the underlying mechanisms of the interaction between resting or stimulated human NK cells with M1 or M2. We observed a lower percentage of activated NK cells that produced less IFN-g upon co-culture with M2. Also, CD56dim NK cells co-cultured with M2 displayed lower degranulation and cytotoxic activity than NK cells co-cultured with M1. Soluble TGF-g and M2-driven up-regulation of CD85j (ILT-2) on NK cells accounted for the diminished IFN-g production by CD56bright NK cells, while M2-driven up-regulation of CD85j on NK cells accounted for the generation of hyporesponsive CD56dim NK cells with limited degranulation and cytotoxic capacity. Accordingly, M2 expressed higher amounts of HLA-G, the main ligand for CD85j, than M1. Hyporesponsiveness to degranulation in NK cells was not restored at least for several hours upon removal of M2. Therefore, alternatively-activated macrophages restrain NK cell activation and effector functions through different mechanisms, leading to NK cells that display diminished IFN- production and at least a transiently impaired degranulation ability. These results unravel an inhibitory circuit of possible relevance in pathological situations.