Regulatory T cells in embryo implantation and the immune response to pregnancy
Sarah A. Robertson, … , Alison S. Care, Lachlan M. Moldenhauer
Sarah A. Robertson, … , Alison S. Care, Lachlan M. Moldenhauer
Published October 1, 2018
Citation Information: J Clin Invest. 2018;128(10):4224-4235. https://doi.org/10.1172/JCI122182.
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Review

Regulatory T cells in embryo implantation and the immune response to pregnancy

Abstract

At implantation, the embryo expresses paternally derived alloantigens and evokes inflammation that can threaten reproductive success. To ensure a robust placenta and sustainable pregnancy, an active state of maternal immune tolerance mediated by CD4+ regulatory T cells (Tregs) is essential. Tregs operate to inhibit effector immunity, contain inflammation, and support maternal vascular adaptations, thereby facilitating trophoblast invasion and placental access to the maternal blood supply. Insufficient Treg numbers or inadequate functional competence are implicated in idiopathic infertility and recurrent miscarriage as well as later-onset pregnancy complications stemming from placental insufficiency, including preeclampsia and fetal growth restriction. In this Review, we summarize the mechanisms acting in the conception environment to drive the Treg response and discuss prospects for targeting the T cell compartment to alleviate immune-based reproductive disorders.

Authors

Sarah A. Robertson, Alison S. Care, Lachlan M. Moldenhauer

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Figure 3

Decidual Tregs facilitate maternal blood vessel adaptation and the transformation of spiral arteries underpinning placental development.

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Decidual Tregs facilitate maternal blood vessel adaptation and the trans...
(A) Decidual uNK cells release IFN-γ to regulate decidual vascular remodeling associated with extravillous trophoblast invasion as well as displacement of endothelial cells and smooth muscle cells (SMCs) (107). Tregs release TGF-β, IL-10, and HO-1 to suppress inflammatory activation and modulate decidual uNK, macrophage, and DC phenotypes (53, 88, 99, 104, 105). The result is reduced vascular resistance and increased blood flow to the developing placenta. (B) When Tregs are deficient, decidual vascular remodeling is impaired (41, 63, 116), particularly when uNK cells are also dysregulated (115). The effects of Treg cell deficiency may be mediated by elevated decidual Th1 and Th17 cells and/or M1 macrophages (41, 97, 99). The result is an elevated synthesis of the proinflammatory cytokines TNF, IL-6, and IL-17 that elicit elevated vascular resistance and permeability, causing inflammatory injury accompanied by elevated soluble Flt (sFlt), soluble endoglin (sEng), VEGF, and NO, which in turn impair placental development, resulting in fetal growth restriction (63, 119, 120). Treg deficiency is thus implicated in contributing to “shallow placentation,” the upstream cause of preeclampsia and other gestational disorders in women (27, 70, 176). ET-1, endothelin-1.