Type 2 and type 3 innate lymphoid cells at the maternal-fetal interface: implications in preterm birth

Abstract

Background Preterm birth (PTB) is one of the major causes of neonatal morbidity and mortality worldwide. It is commonly accepted that the act of giving birth is the final step in a proinflammatory signaling cascade, orchestrated by an intrauterine milieu coupled to hormonal cues. Consequently, the inflammatory process plays a pivotal role during the pathogenesis of human labor, both in term and preterm deliveries. The ability of innate lymphoid cells (ILCs) to act as pro-inflammatory mediators arose the interest to study their role in normal and pathological pregnancies. The aim of this work was to analyze the relative frequencies of ILCs subsets in pregnancy and the levels of IL-4, IL-17, IL-22, and IFN-γ as inflammatory mediators. Accordingly, we hypothesized that changes in the proportions of ILCs subpopulations could be related to preterm birth. Methods We analyzed 15 full-term delivery samples and six preterm delivery samples. In the full-term group (FTB) peripheral blood was taken during routine blood analysis, on 3 occasions: 1st, 2nd and 3rd trimester. After delivery, peripheral blood, cord blood and placenta were collected. In PTB group, peripheral blood samples were obtained on two occasions: before and 24 h after treatment with progesterone. We used flow cytometry to analyze ILCs in maternal peripheral blood, placenta, and cord blood samples. Maternal peripheral blood and cord blood samples were analyzed by enzyme-linked immunosorbent assay for IL-4, IL-17, IL-22, and IFN-γ plasma levels at the time of labor. Results We observed significantly increased relative frequencies of ILC2 and ILC3 in the decidua, as well as an increase of ILC2 in cord blood samples in PTB group, compared to FTB samples. We also found a decrease in IFN-γ in peripheral blood samples of the PTB group, suggesting a functional withdrawal. Additionally, IL-4, IL-17, IL-22 levels were similar in PTB and FTB groups, denoting a relevant role in mediating labor. Conclusion Our results suggest that ILC2 and ILC3 play a role in PTB by mediating an inflammatory response. Further work is necessary to evaluate the importance of ILCs in the regulation of labor.

Circulating Innate Lymphoid Cells Exhibit Distinctive Distribution During Normal Pregnancy

“…Moreover, ILC2 is the most abundant ILC subset in murine uterus [ 22 ], indicating their underline effect in maintaining normal pregnancy. The dynamic changes of ILC subsets in human decidua and murine uterus suggest an important role of ILCs in maintaining healthy pregnancy, and an abnormal increasing of ILC subsets may lead to a pathologic pregnancy, such as preterm labor [ 19 , 23 ].…”

Deciphering decidual leukocyte traffic with serial intravascular staining

“…The question of decidual lymphocyte traffic is especially relevant as human studies suggest that as many as three dNK cells subsets exist, distinguished by cell surface receptors and transcriptional/functional programming ( 13 ). Similarly, innate lymphoid cells (ILCs) have been identified in both the murine ( 11 , 25 , 26 ) and human decidua ( 8 , 27 , 28 ) and have been associated with pre-term birth ( 29 , 30 ). Although ILCs are found in circulation, they are most abundant at mucosal sites ( 31 , 32 ).…”

Oxygen regulates ILC3 antigen presentation potential and pregnancy-related hormone actions

“…This interaction plays a fundamental role in the induction of intestinal commensal bacteria tolerance [49]. Although altered ILCs numbers have been described in disturbed pregnancies, the role of ILCs in fetal tolerance has not been studied extensively yet [50][51][52][53][54][55]. Our group has previously observed that ILCs reduce their antigen presentation potential during pregnancy, and that uterine ILCs retain a low presentation potential [18].…”