Immunoregulatory effects of progesterone on peripheral blood-derived human NK cells involve down-regulation of NKp46

RAUL GERMAN SPALLANZANI; LUCAS EZEQUIEL ROSSI; DAMIAN EZEQUIEL AVILA; CAROLINA INES DOMAICA; ANDREA ZIBLAT; GABRIEL ADRIAN RABINOVICH; MARIANA SALATINO; NORBERTO WALTER ZWIRNER

Ciudad Autónoma de Buenos Aires

Congreso; 1º Congreso Franco-Argentino de Inmunología 2010; 2010

Sociedad Argentina de Inmunología y Sociedad Francesa de Inmunología

Clinical evidence indicates that progesterone Pg and its synthetic analog medroxiprogesterone have pro-tumoral effects through mechanisms that involve a stimulation of tumor growth and suppressive effects on T cells and dendritic cells, a fact that is relevant during pregnancy but that also could be important during the immune response against tumors, in particular some of endocrine origin such as mammary tumors. Pg also affects NK cell responsiveness, inducing apoptosis and suppressing IFN-g production of CD56dim cells in response to IL-12. Thus, the aim of this work was to explore additional mechanisms by which Pg affects NK cell responsiveness. We assessed the responsiveness of isolated human NK cells stimulated with IL-12, IL-15 and IL-18, a combination of cytokines relevant for NK cell activation. Pg 10-6 M, a concentration reached in some microenvironments, inhibited IFN-g secretion by cytokine-stimulated NK cells in a 19.9±7.8%, as assessed by flow cytometry. Such reduction in IFN-g+ cells was observed in CD56dim and CD56bright NK cells (9.4±5.6% and 8.2±2.9% reduction of IFN-g+ cells, respectively). Pg also inhibited the expression of the NK cell activating receptors NKp30, NKp46 and NKG2D, as assessed by flow cytometry, as incubation of NK cells with Pg 10-6 M for 24 h induced a statistically significant down-regulation of NKp46 (SFI without Pg=13.5±4.0 vs. SFI with Pg=10.8±3.4, n=5, p=0.023). For NKp30 and NKG2D, a down-regulatory effect of Pg was also observed although the differences did not reach statistical significance (NKp30: SFI without Pg=7.6±3.2 vs. SFI with Pg=5.9±2.6; NKG2D: SFI without Pg=10.6±1.8 vs. SFI with Pg=8.8±1.4, n=5 for both receptors). Thus, Pg exerts immunosuppressive effects in NK cells that involve a down-regulation of the expression of critical receptors involved in recognition of tumor target cells and the cross-talk with dendritic cells, which may have consequences on their immune surveillance potential.