The Transcription Factor NFIL3 Is Essential for Normal Placental and Embryonic Development but Not for Uterine Natural Killer (UNK) Cell Differentiation in Mice1

Abstract

Mice ablated for the gene encoding the transcription factor Nfil3 lack peripheral natural killer (NK) cells but retain tissue-resident NK cells, particularly in mucosal sites, including virgin uterus. We undertook a time course histological study of implantation sites from syngeneically (Nfil3(-/-)) and allogeneically (BALB/c) mated Nfil3(-/-) females. We also examined implantation sites from Rag2(-/-)Il2rg(-/-) females preconditioned by adoptive transfer of Nfil3(-/-) marrow or uterine cell suspensions to identify the Nfil3(-/-) pregnancy aberrations that could be attributed to nonlymphoid cells. Uterine NKs (UNKs) reactive and nonreactive with the lectin Dolichos biflorus agglutinin (DBA) differentiate, localize, and mature within Nfil3(-/-) implantation sites, although at reduced abundance. The DBA nonreactive UNK cells were enriched following Nfil3(-/-) marrow transplantation. Uterine lumen closure, early embryonic development, and differentiation of antimesometrial decidua were delayed in Nfil3(-/-) implantation sites. Major disturbances to the decidual-trophoblast interface that did not lead to fetal death were attributed to NFIL3 deficiency in trophoblast. At midgestation, vessels of the placental labyrinth were enlarged, suggestive of reduced branching morphogenesis. A major term complication in most Nfil3(-/-) × Nfil3(-/-) pregnancies but not Nfil3(-/-) × Nfil3(+/-) pregnancies was dystocia. These studies highlight the differentiation potential and functions of Nfil3(-/-) UNK cell progenitors and illustrate that much of the implantation site histopathology associated with this strain is due to Nfil3 deletion in nonlymphoid cell lineages.

Innate lymphoid cell function in the context of adaptive immunity

“…Remodeling of murine uterine vasculature requires lymphocytes and IL-15, whereas T cells are not required 13, 44, 45, 46 . Importantly, mice with Nfil3 -deficient lymphocytes exhibit defects in uterine vascular remodeling 13, 47 . Nfil3 -deficient mice lack uterine Eomes + CD49b + CD49a − cNK cells, and have reduced numbers of a second uterine ILC1 subset that expresses CD49a 13 , suggesting that these populations are important for normal vascular remodeling.…”

Natural Killer Cell Reduction and Uteroplacental Vasculopathy

“…40 The independence of Nfil3 has been shown for uNK cell differentiation in mice as well. 42 Tissue-resident NK cells in the liver develop independent of eomesodermin, 43 whereas tissue-resident NK cells in the uterus highly express eomesodermin, 44 suggesting more similarities of uNK cells to circulating NK cells. However, the precise origin of uNK cells remains unclear.…”

Uterine Natural Killer Cell Heterogeneity: Lessons From Mouse Models

“…The arterial defects were rescued in bone marrow (BM) chimeric mice when Rag2 −/− gc −/− recipients received wild-type BM but not BM from interferon-γ-deficient mice. Similarly, Nfil3 −/− mice that lack cNK cells (32), have a smaller MLAp, aberrant uterine arterial modifications, and smaller pups (60,61). Roles for interferon-γ in dNK cellmediated vessel modification have not been confirmed in human studies.…”