The Transcription Factor NFIL3 Is Not Required For Uterine Natural Killer Cell Differentiation But Contributes To Placental And Conceptus Development
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Uterine natural killer (uNK) cells are the most abundant lymphocyte in early human and mouse decidua. UNK cell functions have been deduced by histopathologic comparisons of implantation sites between alymphoid (NK-T-B-), NK cell reconstituted alymphoid (NK+T-B-) and normal NK+T+B+ mice. Circulating (c)NK cells are reported to be absent from C57BL/6 mice genetically ablated for the transcription factor Nfil3 (cNK-T+B+) and these mice experience midgestation Th17 cell-mediated fetal loss when mated by BALB/c males. Recently, tissue resident subsets of NK cells have been described in this mouse. A histological time-course examination of syngeneic Nfil3-/- male x Nfil3-/- female and allogeneic BALB/c-Tg(UBC-GFP)30Scha/J male x Nfil3-/- female pregnancy (gestation day; GD 6.5-15.5) was performed to determine the consequences of a maternal cNK-T+B+ phenotype on pregnancy with an Nfil3-/- or Nfil3+/- conceptus. Whole mount immunofluorescence (WM-IF) was used as an additional technique to provide greater insights at midgestation. Nfil3 is a pleiotrophic factor; to examine Nfil3-dependent uNK cell-specific effects, pregnancies in Nfil3-/- bone marrow engrafted alymphoid mice (BME) were studied. UNK cells were less frequent in Nfil3-/- pregnancies and viability of Nfil3-/- implantation sites (IS) did not differ from wild type (WT) matings. Early gestation pathologies included impaired antimesometrial decidualization (AMD) and delays in lumen closure and embryo development (ED). WM examination revealed an enrichment of CD45+CD11c+ cells at GD 8.5 in Nfil3-/- IS compared to WT. Mid-late gestation placental development, including labyrinth vascular space area and interhemal membrane width, deviated significantly less from WT in allogeneic compared to syngeneic matings. BME and alymphoid placental development was similar to WT. Spiral artery (SA) remodeling did not occur in any experimental mating. Results of the present investigation suggest Nfil3-independent uNK cells do not promote AMD or GD 8.5 ED and cannot remodel SAs. Nfil3 plays a role in placental tissue layer (specifically labyrinth) development possibly through trophoblast-dependent mechanisms. The absence of Nfil3 may promote recruitment or differentiation of CD45+CD11c+ cells in the early gestation implantation site. Although not an effective model for studying NK-T+B+ pregnancy, the Nfil3-/- mouse deepens the understanding of innate lymphoid cells and their respective subsets.