Immune–Metabolic Interactions and T Cell Tolerance in Pregnancy

Abstract

Pregnancy depends on a state of maternal immune tolerance mediated by CD4+ regulatory T (Treg) cells. Uterine Treg cells release anti-inflammatory factors, inhibit effector immunity, and support adaptation of the uterine vasculature to facilitate placental development. Insufficient Treg cells or inadequate functional competence is implicated in infertility and recurrent miscarriage, as well as pregnancy complications preeclampsia, fetal growth restriction, and preterm birth, which stem from placental insufficiency. In this review we address an emerging area of interest in pregnancy immunology–the significance of metabolic status in regulating the Treg cell expansion required for maternal–fetal tolerance. We describe how hyperglycemia and insulin resistance affect T cell responses to suppress generation of Treg cells, summarize data that implicate a role for altered glucose metabolism in impaired maternal–fetal tolerance, and explore the prospect of targeting dysregulated metabolism to rebalance the adaptive immune response in women experiencing reproductive disorders.

Association between Preconception Dietary Fiber Intake and Preterm Birth: The Japan Environment and Children’s Study

“…Studies suggest that an imbalance in Treg function or number could contribute to pregnancy complications, including PTB. In some cases, inadequate Treg activity may lead to an overactive immune response against the developing fetus, triggering inflammation and potentially contributing to PTB [ 42 , 43 , 44 , 45 ]. These findings suggest the importance of Clostridium -induced Tregs in the gut microbiota regarding the occurrence of PTB.…”

Phenotypes of peripheral CD4+ T helper cell subsets in pregnant women with HBeAg-negative chronic asymptomatic HBV carriers

“…It is well known that the foetus is semiallogenic to the maternal host during pregnancy, and maternal-foetal immune tolerance plays a key role in ensuring a successful pregnancy ( Piccinni et al., 2021 ; Moldenhauer et al., 2022 ). Disturbance of the maternal immune system is an important factor that leads to foetal abortion, which mainly involves immune cells and cytokines, such as Tfh, Th1/2/17 and Treg cells, in the peripheral blood of pregnant women ( Wang et al., 2020 ; Monteiro et al., 2021 ; Piccinni et al., 2021 ).…”

Tryptophan metabolism and immune alterations in pregnant Hispanic women with chronic Toxoplasma gondii infection

“…The old concept of a Th-1/Th2 negative skew is simplistic and has been replaced with models that show a strong T regulatory (Treg) bias in pregnancy, associated with Th-1 and Th-17 suppression or a Th-17/Treg balance. 22 Tregs recruited from maternal blood to the fetal-maternal interface secrete anti-inflammatory cytokines such as TGF-beta and IL-10 at the decidua upon implantation, and induce peripheral antigen presenting cells to secrete reduced amounts of IFN-γ and TNF-α, and higher levels of IL-4, IL-5, and IL-10. 23 Pregnancy induced changes in immune tolerance may therefore potentially interfere with the dominant Th-1 and Treg homeostatic mechanisms that normally restrain cysts from producing and releasing T. gondii bradyzoites.…”

“…The immune system in pregnancy promotes maternal‐fetal tolerance but may threaten cell‐mediated containment of bradyzoites within chronic T. gondii cysts. The old concept of a Th‐1/Th2 negative skew is simplistic and has been replaced with models that show a strong T regulatory (Treg) bias in pregnancy, associated with Th‐1 and Th‐17 suppression or a Th‐17/Treg balance 22 . Tregs recruited from maternal blood to the fetal‐maternal interface secrete anti‐inflammatory cytokines such as TGF‐beta and IL‐10 at the decidua upon implantation, and induce peripheral antigen presenting cells to secrete reduced amounts of IFN‐γ and TNF‐α, and higher levels of IL‐4, IL‐5, and IL‐10 23 .…”