4.5 Article

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

Journal

EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 46, Issue 8, Pages 1867-1877

Publisher

WILEY-BLACKWELL
DOI: 10.1002/eji.201545923

Keywords

DC; DEC-205; alpha-Galactosylceramide; Invariant NKT cell; Myometrium

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Funding

  1. Grants-in-Aid for Scientific Research [16K09262] Funding Source: KAKEN

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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 a-galactosylceramide (alpha-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 (female) x BALB/c (male)). 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 alpha-GalCer than in the decidua. IL-12 secreted from alpha-GalCer-activated DEC-205(+) DCs stimulated the secretion of cytokines, including IL-2, IL-4, IFN-gamma, TNF-alpha, 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 alpha-GalCer in iNKT-deficient J alpha 18(-/-) (J alpha 18 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.

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