In vivo dendritic cell depletion reduces breeding efficiency, affecting implantation and early placental development in mice

Abstract

Implantation of mammalian embryos into their mother's uterus ensures optimal nourishment and protection throughout development. Complex molecular interactions characterize the implantation process, and an optimal synchronization of the components of this embryo-maternal dialogue is crucial for a successful reproductive outcome. In the present study, we investigated the role of dendritic cells (DC) during implantation process using a transgenic mouse system (DTRtg) that allows transient depletion of CD11c+ cells in vivo through administration of diphtheria toxin. We observed that DC depletion impairs the implantation process, resulting in a reduced breeding efficiency. Furthermore, the maturity of uterine natural killer cells at dendritic cell knockout (DCKO) implantation sites was affected as well; as demonstrated by decreased perforin expression and reduced numbers of periodic-acid-Schiff (PAS)-positive cells. This was accompanied by disarrangements in decidual vascular development. In the present study, we were also able to identify a novel DC-dependent protein, phosphatidylinositol transfer protein beta (PITPbeta), involved in implantation and trophoblast development using a proteomic approach. Indeed, DCKO mice exhibited substantial anomalies in placental development, including hypocellularity of the spongiotrophoblast and labyrinthine layers and reduced numbers of trophoblast giant cells. Giant cells also down-regulated their expression of two characteristic markers of trophoblast differentiation, placental lactogen 1 and proliferin. In view of these findings, dendritic cells emerge as possible modulators in the orchestration of events leading to the establishment and maintenance of pregnancy.

REVIEW ARTICLE: Th1/Th2/Th17 and Regulatory T‐Cell Paradigm in Pregnancy

“…12 Recent data show that uterine DCs play a central role for successful implantation. 13,14 The number of uterine DCs increases at the implantation period, and depletion of DCs results in severe implantation failure.…”

“…13,14 Surprisingly, depletion of DCs also causes embryo resorption in syngeneic and T-cell-deficient pregnancy, suggesting that DCs appear to govern uterine receptivity independent of the immunological tolerance.…”

Liaison between natural killer cells and dendritic cells in human gestation

“…Animals in these studies present low levels of interleukin (IL)-15 resulting in reduced numbers of and impaired differentiation of NK cells. 9 Moreover, this 5 These authors contributed equally to this work. 1 causes a reduction in interferon-c levels and therefore an inadequate spiral artery remodeling.…”

“…1 causes a reduction in interferon-c levels and therefore an inadequate spiral artery remodeling. 8,9 Additionally, murine data indicate that NK cells are also critical for DC immunogenic functions during pregnancy; NK cell ablation in Fms-related tyrosine kinase 3 ligand-expanded DC mice severely compromised decidual development, upregulated anti-angiogenic growth factors expression such as sFlt1 and PF4, generated an inflammatory environment and led to early pregnancy loss. 10 Although studies with mice demonstrate the importance of DC-NK cell cross-talk, data from human research provide conflicting results.…”

Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus

“…Dendritic cells (DCs), [49,50] macrophages, [51] and uterine NK [52] cells are all involved in this complex regulation of tolerance. Current evidence suggests that Tregs also play an important role in this phenomenon, both in the periphery as well as locally at the FMI.…”