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.

Conflict of interest statement

Conflict of interest: SAR is an inventor on international patent PCT/AU99/00499 and receives royalty income from Origio A/S. SAR and LMM receive research support from Ferring Pharmaceuticals (US).

Figures

Figure 1. Tregs are critical for controlling inflammation in the transition to an antiinflammatory decidual environment necessary for embryo implantation and progression of pregnancy.

Mouse models show that Tregs act to suppress inflammation, prevent adverse effects of antifetal alloantigen Teff cells, and allow vascular adaptations required for placental morphogenesis (39, 41, 62, 63, 82, 87). Tregs arise as a consequence of events during the inflammation-like response in the periconception phase, and their abundance, suppressive function, and stability are impacted by events at conception and in the preimplantation phase (, –85, 135, 137). Tregs sustain an antiinflammatory environment until a decline, associated with the inflammation events of parturition and birth, is triggered (40, 64, 88, 89). Decidual Tregs in pregnant women show kinetics and regulatory mechanisms comparable to those in mice (, –54, 56, 58, 59). Recurrent implantation failure, recurrent miscarriage, preeclampsia, and in utero growth restriction are all linked with insufficient numbers, reduced suppressive function and/or instability of Tregs (–21, 23, 24), and excessive inflammation in the uterus and/or gestational tissues (21, 27, 80).

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.

(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 (–110). Treg phenotype and stability are reinforced by IDO and TSLP from tDCs and trophoblasts (111). gal-1, galectin-1; P4, progesterone.

Figure 3. Decidual Tregs facilitate maternal blood vessel adaptation and the transformation of spiral arteries underpinning placental development.

(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.