title: α-Galactosylceramide-activated murine NK1.1(+) invariant-NKT cells in the myometrium induce miscarriages in mice.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.|Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ichikawa
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.|Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Negishi
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeshita
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000022:Abortion, Spontaneous / Q000139:chemically induced*; D000818:Animals; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000009:adverse effects*; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000008:administration & dosage / Q000009:adverse effects*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009215:Myometrium / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology*; D011247:Pregnancy
chemical_list: D016207:Cytokines; D005699:Galactosylceramides; C493154:alpha-galactosylceramide; D018664:Interleukin-12
keywords: DC; DEC-205; Invariant NKT cell; Myometrium; α-Galactosylceramide