Invariant NKT Cell Activation Induces Late Preterm Birth That Is Attenuated by Rosiglitazone

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. Although intra-amniotic infection is a recognized cause of spontaneous preterm labor, the noninfection-related etiologies are poorly understood. In this article, we demonstrated that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of α-galactosylceramide (α-GalCer) induced 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. Peroxisome proliferator-activated receptor (PPAR)γ 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 downregulation 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 dendritic cells to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of α-GalCer also upregulated 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 noninfection-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.