The Immunomodulatory Role of Regulatory T Cells in Preterm Birth and Associated Pregnancy Outcomes

Abstract

Spontaneous preterm birth (sPTB), defined as live birth before 37 weeks of gestational age, is associated with immune dysregulation and pro-inflammatory conditions that profoundly impact newborn health. The question of immune integrity at the maternal-foetal interface is a focus of recent studies centring not only sPTB but the conditions often affiliated with this outcome. Regulatory T cells (Tregs) play a critical anti-inflammatory role in pregnancy, promoting foetal tolerance and placentation. Due to this gestational role, it is hypothesised that decreased or dysfunctional Tregs may be implicated in cases of sPTB. This review examines studies comparing Treg presence in healthy term pregnancies and those with sPTB-associated conditions. Conflicting findings across different conditions and within sPTB itself have been identified. However, notable findings from the research indicate increased proinflammatory cytokines in pregnancies suffering from premature rupture of membranes (pPROM), chorioamnionitis, infection, preeclampsia, and gestational diabetes (GDM). Additionally, reduced Treg levels were identified in preeclampsia, GDM, and pPROM as well as chorioamnionitis presenting with increased Treg dysfunctionality. Treg deficiencies may contribute to health issues in preterm newborns. Current sPTB treatments are limited, underscoring the potential of in utero therapies targeting inflammation, including T cell interventions. Future research aims to establish consensus on the role of Tregs in sPTB and associated conditions and advancing understanding of mechanisms leading to Treg deficiencies in adverse pregnancy outcomes.

Keywords: Tregs; pregnancy immunology; spontaneous preterm birth.

Figure 1

Suppressive mechanisms elicited by Tregs. Tregs can elicit their immunosuppressive functions through various mechanisms. These include the expression of co-inhibitory external markers such as PD-1 or CTLA-4 through cell:cell contact and the production of anti-inflammatory cytokines IL-10 and TGF-β. This allows for the inhibition of the function and maturation of DC and overall immunosuppression of pro-inflammatory effector T cells (Teffs). This image was created in BioRender, adapted from Kempkes, R. W. M., Joosten, I., Koenen, H. J. P. M., and He, X., 2019 [19].