Impact of Th1/Th2 cytokine polarity induced by invariant NKT cells on the incidence of pregnancy loss in mice

Objective: This study aimed to investigate the association of Th1/Th2 polarity induced by CD1d-restricted invariant natural killer T (iNKT) cells with pregnancy outcome. Methods: Two types of iNKT cell stimulants with different cytokine induction properties, alpha-galactosylceramide (AGC; Th1-biased inducer), and a sphingosine-truncated derivative of AGC (OCH; Th2-biased inducer) were administered to pregnant mice on day 9.5 post-coitus (pc), and the incidence of pregnancy loss was evaluated. Serum Th1/Th2 cytokine levels after the iNKT cell stimulations were assessed. Cytokine production from cultured splenocytes following iNKT cell activation was analyzed. Results: No fetal loss was observed after OCH administration, in clear contrast with the high frequency of pregnancy loss after AGC exposure. High serum levels of IL-4 and IL-10 were detected upon OCH administration, whereas a temporary surge of IFN-gamma was observed after AGC administration. In splenocyte cultures, increases in IL-4 and IL-10 were noted after OCH administration, whereas IL-12 production was enhanced by AGC. Additionally, AGC-induced pregnancy loss was inhibited by IL-4 administration. Conclusion: The resistance of mouse pregnancy to iNKT cell stimulation by OCH and the prevention of AGC-induced fetal loss by IL-4 were demonstrated. In pregnancy, the regulation of Th1/Th2 polarity by iNKT cells is a key to healthy fetal growth.