Regulatory effects of alpha7 nicotinic receptor on human NK cells

ZANETTI, S.; ZIBLATT, A.; ZWIRNER, N.; BOUZAT, C.

Buenos Aires

Congreso; Segundo Congreso Franco Argentino de Inmunología - LXIII Reunión Anual de SAI - IV Reunión Anual de la Sociedad Latinoamericana de Inmunodeficiencias (LASID); 2015

Sociedad Franco Argentino de Inmunología - SAI - Sociedad Latinoamericana de Inmunodeficiencias (LASID)

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that mediate calcium (Ca2+) influx and diverse intracellular signals in neuronal and non-neuronal cells. Previously, we determined by PCR and qPCR that the expression of α7 nAChR mRNA increases 3-fold after activation of NK cells with IL-12, IL-18 and IL-15. Also, cell surface expression of α7 nAChR is detected using Alexa488-labeled α-bungarotoxin (α-BGT, a specific antagonist of α7) in cytokine-stimulated but not in resting NK cells. In the present study, we investigated the functionality of α7 nAChR in NK cells as well as the regulation by agonists and antagonists of α7 of their effector functions elicited by cytokines. By confocal microscopy, we determined that in cytokine-stimulated NK cells the presence of PNU-282987 (a specific agonist of α7) and nicotine plus PNU-120596 (a specific positive allosteric modulator of α7) induces rapid increase of intracellular Ca2+, indicating that α7 nAChR is functional in these cells. This effect is not observed in the absence of the α7 nAChR ligands or in cells preincubated with α-BGT. We also observed that in cytokine-stimulated NK cells the presence of PNU-282987: i) down-regulates the expression of NKG2D, ii) reduces the production of IFN-γ, and iii) does not affect the NK cell-mediated cytotoxicity against K562 target cells. Overall, our results indicate that IFN-γ production and phenotype of NK cells can be negatively regulated by activation of α7 nAChR. These effects may contribute to tumor progression or dissemination of intracellular infections where NKG2D and IFN-γ play a critical role.