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
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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 2

Tregs arise as a result of events initiated at conception, resulting in the recruitment of pTreg and tTreg populations into the uterine decidua at embryo implantation.

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Tregs arise as a result of events initiated at conception, resulting in ...
(i) Estrogen (E2) and seminal fluid induce the recruitment of macrophages and DCs, which acquire M2 and tDC phenotypes in response to TGF-β and prostaglandin (PGE) in seminal fluid; granulocyte-macrophage CSF (GM-CSF) and chemokines released by uterine epithelial cells; and IFN-γ and IL-10 originating in uNK cells (38, 105, 128). tDCs take up paternal alloantigens in seminal fluid and traffic to the uterus-draining PALNs (90). (ii) In the PALNs, tDCs present antigen to naive Th0 cells, which become activated, proliferate, and differentiate into pTregs before release into the peripheral blood (39, 84, 90, 137). (iii) An expanded pool of peripheral blood pTregs and tTregs (41, 83, 139) is recruited and retained in the uterus prior to and during embryo implantation in response to epithelial cell–derived CCL3, CCL4, CCL5, and CCL19 (85, 137). Here, Tregs inhibit the activation and function of Th1 and Th17 cells by sequestering IL-2 and other suppressive mechanisms (53, 88, 99, 100) and control inflammation by the release of TGF-β, IL-10, and HO-1 to interact with DCs and uNKs (53, 88, 99, 104, 105). This in turn impairs Th1 survival, promotes further Treg generation (39, 102, 103, 105), and potentially influences decidual transformation and receptivity to embryo implantation (108–110). Treg phenotype and stability are reinforced by IDO and TSLP from tDCs and trophoblasts (111). gal-1, galectin-1; P4, progesterone.