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

• The aryl hydrocarbon receptor in decidual NK cells was significantly increased in RSA. • AhR+ NK cells expressed significantly higher levels of NKP30, NKP44, NKG2D, perforin, granzyme B and IFN-γ in both peripheral blood and decidua. • Kynurenine promoted the NKP30, NKP46, perforin, or granzyme B in pNK and dNK cells. • Proinflammatory factors, including LPS, TNF-α and IL-1β, up-regulate the AhR expression and further increase the NKP46 level in dNK cells. 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-γ) 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-α, IL-β 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. [ABSTRACT FROM AUTHOR]