Kynurenine promotes the cytotoxicity of NK cells through aryl hydrocarbon receptor in early pregnancy

During early pregnancy, decidual NK (dNK) cells play indispensable roles in many processes including the decidualization, the implantation, and the maintenance of immune tolerance. Abnormal cytotoxic activity of NK cells can cause recurrent spontaneous abortion (RSA), while the regulatory mechanism of NK cytotoxicity remains to be unclear. In this study, we found that kynurenine in decidua and villus was in a comparable level between patients with RSA and normal pregnancy women. However, the aryl hydrocarbon receptor (AhR) in decidual NK cells was significantly increased in RSA. Compared with AhR NK cells, cytotoxic activity-related molecules (NKP30, NKP46, NKG2D, perforin, granzyme B and IFN-gamma) was highly expressed in both AhR(+) peripheral and decidual NK cells, and kynurenine stimulation promoted the expression of killer receptors and the cytoplasmic granules in an AhR-dependent manner. Stimulation with TNF-alpha, IL-beta and LPS upregulated the AhR expression in dNK cells in vitro. These results indicate that kyn/AhR signal enhances the cytotoxicity of NK cells, and increased expression of AhR may be an induction factor of RSA.