In vivoactivation of invariant natural killer T cells induces systemic and local alterations in T-cell subsets prior to preterm birth

Abstract

Preterm birth, the leading cause of neonatal morbidity and mortality worldwide, is frequently preceded by spontaneous preterm labour, a syndrome of multiple aetiologies. Pathological inflammation is causally linked to spontaneous preterm labour. Indeed, direct activation of invariant natural killer T (iNKT) cells via α-galactosylceramide induces preterm labour/birth largely by initiating systemic and local (i.e. decidua and myometrium) innate immune responses. Herein, we investigated whether iNKT-cell activation altered local and systemic T-cell subsets. Administration of α-galactosylceramide induced an expansion of activated CD1d-restricted iNKT cells in the decidua and a reduction in the number of: (1) total T cells (conventional CD4 and CD8 T cells) through the down-regulation of the CD3ɛ molecule in the peripheral circulation, spleen, uterine-draining lymph nodes (ULNs), decidua and/or myometrium; (2) CD4 regulatory T cells in the spleen, ULNs and decidua; (3) T helper type 17 (Th17) cells in the ULNs but an increase in the number of decidual Th17 cells; (4) CD8 regulatory T cells in the spleen and ULNs; and (5) CD4 and CD8 forkhead box protein 3 negative (Foxp3 ) responder T cells in the spleen and ULNs. As treatment with rosiglitazone prevents iNKT-cell activation-induced preterm labour/birth, we also explored whether the administration of this peroxisome proliferator-activated receptor gamma (PPARγ) agonist would restore the number of T cells. Treating α-galactosylceramide-injected mice with rosiglitazone partially restored the number of T cells in the spleen but not in the decidua. In summary, iNKT-cell activation altered the systemic and local T-cell subsets prior to preterm labour/birth; however, treatment with rosiglitazone partially reversed such effects.

IL-1 signaling mediates intrauterine inflammation and chorio-decidua neutrophil recruitment and activation

“…In contrast with our findings, studies in mouse models of preterm birth have demonstrated changes in frequency and proinflammatory and prolabor function for T cells, iNKT cells, and Tregs in the chorio-decidua, implicating these cells in the pathogenesis of inflammation-mediated preterm birth (59)(60)(61)(62). Besides species differences, different route (systemic vs. IA route in our study) of administration of proinflammatory agents might explain these different findings.…”

The immunophenotype of decidual macrophages in acute atherosis

“…During early and mid‐pregnancy, macrophages displaying an alternative or M2‐like phenotype are the dominant decidual subset, indicating that such cells may play an important role in maternal‐fetal tolerance throughout pregnancy . At the end of gestation, during the physiological process of labor, decidual macrophages acquire an M1‐like phenotype, a phenomenon that also occurs during the pathological process of preterm labor and coincides with the infiltration of other inflammatory cells at the maternal‐fetal interface . Disruption of the decidual macrophage population has been linked to placental dysfunction and disease .…”

CD71+ erythroid cells from neonates born to women with preterm labor regulate cytokine and cellular responses

“…In addition, maternal CD8+ regulatory T cells have been implicated in the systemic and local (i.e. the maternal-fetal interface) immune mechanisms that lead to spontaneous preterm labor [70, 71]. CD8+ regulatory T cells are induced extrathymically through antigen presentation in the neonatal period in mice [72]; however, their role in humans is unknown.…”