Infectious Diseases in Obstetrics and Gynecology While uNK cells, macrophages, and dendritic cells aid to orchestrate the balance between pro- and anti-inﬂammatory milieu over the course of gestation, T regulatory cells Tregs in the uterus are thought to be mainly immunosuppressive. Studies demonstrate the importance of these cells as adoptive transfer of Tregs into abortion prone mice leads to pregnancy rescue [34]. T-cell-deﬁcient Rag1−/− mice given the TLR4 agonist LPS deliver preterm. Infusion of Tregs into these mice rescues pregnancy to term, indicating an advantageous role for these cells in TLR-pathogen mediated response to adverse pregnancy outcomes [35]. The function and phenotype of T regs found in the uterus remains unknown, but these cells are presenting as a possible therapeutic cell to aid in rescue of pregnancy loss. While the aforementioned cellular activities are highly orchestrated throughout pregnancy and particularly during the onset of labor, these actions are correlated to speciﬁc hormonal cues that allow for these changes. For the majority of pregnancies one of the main mechanisms that allows for uterine quiescence and lack of uterine muscle movement is the increased presence of the hormone progesterone [36, 37]. Female sex hormones have been shown to decrease the T- cell stimulatory capacity of DCs during pregnancy [38]. In rodents, direct treatment of DCs with progesterone has been shown to increase the inhibitory capacity of DCs and these changes are associated with progesterone receptor (PR) regulation. Due to the fact that human and murine uNK cells do not possess PRs, the capacity of DCs to produce IL-15 for uNK development may work through indirect mediation of DCs by progesterone [39, 40]. Importantly, macrophages possess PR and are directly regulated by progesterone as their migration and nitric oxide production is severely impaired when progesterone levels are high. In support of these ﬁndings, PR/ mice show high levels of macrophage and neutrophil inﬁltration in the pregnant uterus [3]. Taken together, the functional withdrawal of progesterone is critical to the initiation of parturition as its decreased action allows for control of immune cells needed to initiate inﬂammatory cascades to be relinquished. 3. Preterm Birth: Activated Uterine Immunity How does the presence of viral or bacterial organisms lead to preterm birth? It is rarely the foreign organism itself that causes preterm birth. Rather, it is the immune response of the host evoked by the pathogen that leads to aberrant pregnancy outcomes. With the knowledge of parturition as a process mediated by inﬂammation, we can begin to understand that pathogenic insults can trigger unscheduled uterine immunity. Evidence demon- strates that the activated TLR pathways and the route of pathogenic entry may determine the immunological cascade of aberrant cellular and cytokine activity that lead to preterm birth ([11–15], our unpublished data). The majority of these pathways commonly lead to increased NF-κB activity that allows for production of inﬂamma- tory cytokines and mediation of progesterone withdrawal through modulation of the participation of diﬀerent PRs [20]. 3 Brieﬂy, the immune system at the maternal-fetal interface thus far has been discussed due to its virtue as specialized toward growth and decidualization of the placental organ and delicately regulated by sex hormones. However, new observations have deciphered that innate immune defenses, characteristic of innate immunity on peripheral blood cells, are present at the placental level as well. The TLRs are expressed at the placental level on trophoblasts, uNK cells, DCs, and macrophages [17, 21]. Activation of any of the TLRs leads to a downstream cascade of proinﬂammatory cytokine production, and most notably, to activation of the NF-κB transcription factor. It stands to reason that TLR activation at the maternal-fetal interface may tip the tightly regulated cytokine and hormonal anti-inﬂammatory milieu necessary for successful term pregnancy. Two forms of pathogenic entry are studied in rodent models due to their correlations with human infection. Intrauterine ascension through the vaginal tract and systemic inﬁltration are mimicked by intrauterine infusion and intraperitoneal injections, respectively (Figure 1). Bacteria show stronger correlations throughout the literature with increased incidence of preterm birth than viruses. This may be due to the diﬀerential sites of infection that bacteria versus viruses target. Generally, bacteria are found in mucosal membranes that surround the amniotic sac or those lining the intrauterine canal [8]. On the other hand, reports demonstrate that viruses, in need of host cell machinery for replication, tend to infect trophoblast cells of the placenta as these cells possess speciﬁc receptors needed for viral particle entry [41–43]. Importantly, bacteria are easily cultured from amniotic ﬂuid or from swab samples taken from the uterine tracts of pregnant women [7, 44]. Due to the nature of viruses, these pathogens are more diﬃcult to pinpoint, though some studies have been able to isolate HIV and adenovirus from amniotic ﬂuid samples [8, 45]. 4. Bacterial Entry Bacterial infections manifest in the pregnant uterus generally between maternal and fetal membranes or directly within amnion or chorion speciﬁc fetal membranes. Infection of the amniotic cavity is denoted amnionitis, direct infection of fetal membranes is denoted chorioamnionitis; whereas funisitis is infection of the umbilical cord. Interestingly, several reports note that bacterial agents are rarely found at the placental level, in contrast to viral pathogens [7, 8, 45]. Due to the fact that bacteria can subsist extracellularly within membranes, it is reasonable to postulate that intrauterine bacteria or fetal DNA due to necrosis of fetal cells are visualized by TLRs that are extracellular such as TLR2, TLR4, TLR5, and TLR6 [46, 47]. Eﬀective methods of probing for the presence of bacterial agents are immunostaining of membranes of the chorion or amnion from term versus preterm deliveries. Membranes from preterm delivered placentas show higher levels of chemotactic proteins MCP-1 and CXCL6 (Granulocyte chemotactic protein-2), inﬂammatory cytokines IL-1β, TNF- α, and COX-2 by immunohistochemical staining [48–50].