Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment?

Abstract

Background: Adaptation of the maternal immune response to accommodate the semi-allogeneic fetus is necessary for pregnancy success, and disturbances in maternal tolerance are implicated in infertility and reproductive pathologies. T regulatory (Treg) cells are a recently discovered subset of T-lymphocytes with potent suppressive activity and pivotal roles in curtailing destructive immune responses and preventing autoimmune disease.

Methods: A systematic review was undertaken of the published literature on Treg cells in the ovary, testes, uterus and gestational tissues in pregnancy, and their link with infertility, miscarriage and pathologies of pregnancy. An overview of current knowledge on the generation, activation and modes of action of Treg cells in controlling immune responses is provided, and strategies for manipulating regulatory T-cells for potential applications in reproductive medicine are discussed.

Results: Studies in mouse models show that Treg cells are essential for maternal tolerance of the conceptus, and that expansion of the Treg cell pool through antigen-specific and antigen non-specific pathways allows their suppressive actions to be exerted in the critical peri-implantation phase of pregnancy. In women, Treg cells accumulate in the decidua and are elevated in maternal blood from early in the first trimester. Inadequate numbers of Treg cells or their functional deficiency are linked with infertility, miscarriage and pre-eclampsia.

Conclusions: The potency and wide-ranging involvement of Treg cells in immune homeostasis and disease pathology indicates the considerable potential of these cells as therapeutic agents, raising the prospect of their utility in novel treatments for reproductive pathologies.

Figure 1

The microenvironmental context in which naive CD4⁺ Th0 cells encounter their cognate antigen is a principal determinant of their differentiation fate and development into Treg cells as opposed to Th1, Th2 or Th17 cells. Treg cells confer a tolerogenic immune response whereas Th1, Th2 and Th17 cells mediate protective immunity. Signals originating from the DC presenting antigen to the Th0 cell, as well as the relative concentrations of key cytokines in the immediate vicinity, are instrumental. DC, dendritic cell; IL, interleukin; Th1, Th2 and Th17, T-helper type 1, type 2 and interleukin 17-producing Th cell; TGF, transforming growth factor.

Figure 2

Treg cells are selected in the thymus when the avidity of their TCR for self-MHC is lower than the threshold for negative selection by apoptosis, but higher than the threshold for positive selection of effector T cells.

Figure 3

Deficiency in Treg cell numbers and/or suppressive function are associated with infertility, recurrent spontaneous abortion and pre-eclampsia in women. Studies in mouse models show that in normal pregnancy, adequate Treg cell function acts to suppress Th1-mediated maternal attack of the semi-allogeneic conceptus, but Treg cell depletion leads to insufficient suppression and Th1-mediated fetal loss.

Figure 4

A working model of the key steps in the induction and effector pathways of Treg cell activation, expansion and suppressive function to mediate maternal–fetal tolerance. The sequence of events includes (1) antigen uptake and processing within tolerogenic DCs; (2) trafficking of DCs to draining lymph nodes and presentation of antigen fragments on the surface of the DC in association with MHC molecules; (3) interaction between the DC and Treg cells expressing cognate TCRs in the presence of IL-2 and/or IL-15 to elicit their activation and proliferation; (4) recruitment of Treg cell populations from the maternal circulation into the decidual tissue mediated by CCL4 and (5) exertion of specific effector functions, including secretion of IL-10 and TGFβ, and inducing IDO expression in target DCs to further activate and maintain suppressive function in Treg cells, inhibit Th1 cell proliferation and induce Th1 cell apoptosis. Specific cytokines including TGFβ, GM-CSF, IL-4, IL-10, G-CSF and prostaglandin E known to predominate the uterine cytokine milieu are identified as regulators of tolerogenic DCs. Ag, antigen; CCL4, chemokine (C–C motif) ligand 4; DC, dendritic cell; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; MHC, major histocompatibility complex; TGF, transforming growth factor.

Figure 5

Several strategies for increasing Treg cell activity are in development as novel tissue transplantation therapies or treatments for autoimmune disease, and analogous approaches might have applications in reproductive medicine. These include (1) administration of IDO-inducing agents or cytokines (such as G-CSF) to expand the pool of tolerogenic DCs; (2) delivery of tolerogenic DCs after pulsing with specific antigen; (3) delivery of antigen in a form such as apoptotic cellular material known to stimulate Treg proliferation and (4) delivery of antigen-specific Treg cells after recovery and ex vivo expansion. DC, dendritic cell.