Resistance to Lipopolysaccharide-Induced Preterm Delivery Mediated by Regulatory T Cell Function in Mice1

Abstract

Intrauterine or intraperitoneal administration of lipopolysaccharide (LPS) into normal mice at midgestation induces preterm delivery (PTD) within 24 h through a mechanism dependent on Toll-like receptor signaling and expression of inflammatory cytokines. The exact participants in the cellular network involved in PTD are not known. Although the activities of innate immune cells are thought to be important, the extent to which this process depends on T and B cells has yet to be examined. Mice deficient in T and B cells due to genetic deficiency in the recombination activating gene 1 (Rag1(-/-)) were given LPS intraperitoneally on Day 15 of gestation and found to be susceptible to LPS-induced PTD. This was found to involve many of the inflammatory mediators reported as important in normal mice. Moreover, at a low dose (3 microg), pregnant Rag1(-/-) mice were found to be more susceptible to PTD than a cohort of normal mice on the same genetic background. This increased susceptibility was partially reversed by transfer, on Day 10 of gestation, of whole lymphocytes or purified CD4(+) T cells. Transfer of purified CD4(+) T cells to Rag1(-/-) mice resulted in a uterine draining node population of FOXP3(+) cells, suggesting that these cells may contribute to resistance to LPS-induced PTD. Overall, the data suggest that, although T and B lymphocytes are not critical positive regulators of LPS-induced PTD, CD4(+) T cells play a protective and regulatory role, and thus could be a target for preventive or therapeutic manipulation.

PD-1 Regulates T Cell Proliferation in a Tissue and Subset-Specific Manner During Normal Mouse Pregnancy

“…We used flow cytometry to determine the expression of PD-1 on gestational days 5, 8 and 15 and compared it to unmated littermates. These gestational days were chosen because implantation occurs on day 5, placental remodeling occurs around day 8, and day 15 is an important time-point for sensitivity to LPS induced preterm delivery (Bizargity et al, 2009). In these experiments the uteri of antibody treated mated non-pregnant (MNP) mice were used as controls because there is evidence that exposure to male antigens in seminal fluid during mating can induce proliferation of antigen-specific T cells (Moldenhauer et al, 2009).…”

Chronic inflammatory lesions of the placenta are associated with an up-regulation of amniotic fluid CXCR3: A marker of allograft rejection

“…Fetal antigen-specific Tregs (regulatory T cells) maintain maternal-fetal tolerance throughout pregnancy [3,4,124]. In contrast, effector T cells infiltrate into the maternal-fetal interface and are implicated in the processes of term [65,[125][126][127] and preterm [17,25,[128][129][130] parturition.…”

Impact of Immune Deficiency on Remodeling of Maternal Resistance Vasculature 4 Weeks Postpartum in Mice

“…[21][22][23][25][26][27] There may be accumulation of TREGs in PP that may protect subsequent pregnancies. 28,29 Abnormal pregnancy, including preeclampsia [30][31][32][33][34][35] and preterm birth, 36 is associated with immune system dysregulation. Moreover, T-cell subset manipulation has revealed and modified cardiovascular abnormalities during normal rodent pregnancy 37 and in rodent models of pregnancy-associated hypertension.…”