During pregnancy in mice, uterine natural killer (uNK) cells abundantly accumulate on the mesometrial side of the placenta. In this study, we show that the presence of both mature and immature uNK cells requires IL-15. Bone marrow transplantation of NK cell-negative mice due to null mutations in the recombination-activating gene (Rag) 2/common cytokine receptor γ-chain (Rag2−/−γc−/−) genes indicated that uNK cells originate from the bone marrow and require IL-15 to develop. NK cells are thought to be central players in the immune response to intracellular pathogens such as Listeria monocytogenes, a bacterium that also has a predilection for replication in the placenta. However, IL-15−/−, NK cell-deficient mice were relatively protected from this infection compared with wild-type mice, and during pregnancy the absence of NK cells did not compromise the immune response at this site. The loss of uNK cells results in decidual abnormalities, including thickening of the arterial walls with luminal narrowing and a hypocellular decidua basalis. These defects were rescued by bone marrow transplantation of the Rag2−/−γc−/− mice that restored the uNK cell population. The decidual abnormalities in the IL-15−/− mice however did not result in infertility as gestation times and litter sizes were comparable to those of wild-type mice. Fetal weights were mildly compromised, consistent with the arterial pathologies. These results show that uNK cells are not required for successful pregnancy and that NK cells are not essential for an adequate immune response to L. monocytogenes in either pregnant or nonpregnant mice.

The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) is expressed in macrophages that have been differentiated in the presence of CSF-1 and is important in the containment of intracellular pathogens. IDO also appears to play a role in suppression of T cell responses in a variety of contexts. In the placenta, its enzymatic activity is believed to establish a chemical barrier that protects the fetal allograft from T cell-mediated immune aggression. We have studied the regulation of IDO in the utero-placental unit of mice following infection with the Gram-positive, intracellular bacterium Listeria monocytogenes that has a predilection for replication in the decidua basalis. IDO mRNA and protein expression is enhanced in the utero-placental unit following infection with L. monocytogenes. However, in contrast to the human where IDO is expressed by the CSF-1R-positive syncytial trophoblast, IDO is not expressed in murine trophoblastic tissue but instead is found in stromal cells of the decidua basalis and metrial gland and following infection, in endothelial cells. Using mice carrying null mutations in cytokine/growth factor genes, we explored the regulation of IDO in the placenta. Consistent with the absence of CSF-1R expression in the IDO-expressing cells of mice, neither the basal levels of IDO nor its induction following infection is affected by the absence of CSF-1. However, although the basal level of IDO is normal, the enhanced expression during Listeriosis is completely abrogated in the absence of IFN-γ, a cytokine required for the resolution of this infection. These data suggest that IDO plays a role in resolving bacterial infection in the placenta while at the same time maintaining a barrier to T cells whose presence might result in fetal rejection.

The fetal allograft poses an immunological challenge: how is it protected while immunity to pathogens, particularly those that replicate in the placenta, is maintained? Several theories have been proposed to explain this fetal protection, including a pregnancy-based bias towards a Th2 rather than Th1 cytokine profile in order to avoid generating cytotoxic T cells that could threaten the fetus. Listeria monocytogenes preferentially replicates in the placenta and systemically requires a Th1 response for sterile eradication. In the placenta, the Th1 cytokines tumor necrosis factor alpha (TNF-␣) and gamma interferon (IFN-␥) are also synthesized in response to this pathogen, without fetal loss. Here we show, by using mice homozygous for null mutations in either the cytokine or cytokine receptor genes, a requirement for both TNF-␣ and IFN-␥ signaling for an effective placental immune response to L. monocytogenes. However, T cells were not recruited to the placenta. Genetic studies in which the fetal component of the placenta was genetically different from the mother indicated that both the production of and response to these cytokines were maternal. Despite the requirement for these cytokines, the early recruitment of neutrophils to the placenta was normal. Consequently, the bacterium appeared to be delayed in its colonization of this organ and did not fully gain hold until 72 h postinfection. These data show a requirement for Th1 cytokines during pregnancy for effective immunity and indicate that a bias away from Th1 cytokine synthesis is not a necessary prerequisite of pregnancy.

No abstract