Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality; however, its non-infection-related mechanisms are poorly understood. Herein, we show that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of α-galactosylceramide (α-GalCer) induces late PTB and neonatal mortality. In vivo imaging revealed that fetuses from mice that underwent α-GalCer-induced late PTB had bradycardia and died shortly after delivery. Yet, administration of α-GalCer in the second trimester did not cause pregnancy loss. PPARγ activation, through rosiglitazone treatment, reduced the rate of α-GalCer-induced late PTB and improved neonatal survival. Administration of α-GalCer in the third trimester suppressed PPARγ activation as shown by the down-regulation of Fabp4 and Fatp4 in myometrial and decidual tissues, respectively; this suppression was rescued by rosiglitazone treatment. Administration of α-GalCer in the third trimester induced an increase in the activation of conventional CD4+ T cells in myometrial tissues and the infiltration of activated macrophages, neutrophils and mature DCs to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of α-GalCer also up-regulated the expression of inflammatory genes at the maternal-fetal interface and systemically, and rosiglitazone treatment partially attenuated these responses. Finally, an increased infiltration of activated iNKT-like cells in human decidual tissues is associated with non-infection-related preterm labor/birth. Collectively, these results demonstrate that iNKT-cell activation in vivo leads to late PTB by initiating innate and adaptive immune responses and suggest that the PPARγ pathway has potential as a target for prevention of this syndrome.
Objective: Maternal-fetal tolerance involves a tight balance between the innate and adaptive immunity, which avoids rejection of the semi-allogeneic embryo. The innate and adaptive limbs of the immune response are bridged by iNKT cells; therefore, we hypothesized that an alteration in their number and/or activation breaks maternal-fetal tolerance, leading to premature delivery. Methods: Pregnant mice were injected on E16.5 with either α-galactosylceramide (an iNKT activator; 2 μg) or PBS as a control (n=19 each). Gestational length and the rates of stillbirth and long-term pup survival were recorded. Peripheral blood, decidua, liver, spleen and lymph nodes were collected just prior to delivery from additional treated and control mice (n=8-9 each). In tissue cell suspensions, iNKT phenotype and activation were analyzed by flow cytometry. Results: 1) iNKT activator treatment promoted premature delivery (E18.09±0.60; controls delivered on E19.51±0.78); 2) iNKT activator treatment increased the rate of stillbirth (63.63 vs. 21.94%); 3) iNKT activator treatment did not reduce long-term pup survival; 4) iNKT activator treatment caused an expansion of iNKT cells (CD1d tetramer+NK1.1+CD49b+) in peripheral blood, liver and decidua, but not in spleen and lymph nodes; 5) iNKT cell activation was unchanged by iNKT activator treatment. Conclusion: Treatment with α-galactosylceramide causes an expansion of systemic and local iNKT cells leading to premature delivery in mice.
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