α‐Galactosylceramide‐activated murine NK1.1+ invariant‐NKT cells in the myometrium induce miscarriages in mice

Innate immunity, which is unable to discriminate self from allo‐antigens, is thought to be important players in the induction of miscarriages. Here, we show that the administration of IL‐12 to syngeneic‐mated C57BL/6 mice on gestation day 7.5 (Gd 7.5), drives significant miscarriages in pregnant females. Furthermore, the administration on Gd 7.5 of α‐galactosylceramide (α‐GalCer), which is known to activate invariant natural killer T (iNKT) cells, induced miscarriages in both syngeneic‐mated C57BL/6 mice and allogeneic‐mated mice (C57BL/6 (♀) × BALB/c (♂)). Surprisingly, the percentages of both DEC‐205⁺ DCs and CD1d‐restricted NK1.1⁺ iNKT cells were higher in the myometrium of pregnant mice treated i.p. with α‐GalCer than in the decidua. IL‐12 secreted from α‐GalCer‐activated DEC‐205⁺ DCs stimulated the secretion of cytokines, including IL‐2, IL‐4, IFN‐γ, TNF‐α, perforin, and granzyme B, from the NK1.1⁺ iNKT cells in the myometrium, leading to fetal loss in pregnant mice. Finally, the i.p. administration of IL‐12 and/or α‐GalCer in iNKT‐deficient Jα18(‐/‐) (Jα18 KO) mice did not induce miscarriages. This study provides a new perspective on the importance of the myometrium, rather than the decidua, in regulating pregnancy and a mechanism of miscarriage mediated by activated DEC‐205⁺ DCs and NK1.1⁺ iNKT cells in the myometrium of pregnant mice.