Immune surveillance of the maternal/fetal interface: controversies and implications

Abstract

How the fetal 'allograft' avoids rejection during pregnancy remains a major unresolved immunological paradox. Recent work has suggested that fetomaternal tolerance is in fact maintained by a number of redundant mechanisms, but their relative importance has remained poorly defined. In this paper, I discuss an emerging controversy regarding the ability of maternal T cells to mediate fetal rejection at a time when they appear to be ignorant of fetal and placental antigens. This paradox within a paradox highlights two major research directions in the field of reproductive immunology that, when ultimately reconciled, promise to give significant insight into mechanisms of impaired fertility and compromised fetal and maternal health.

Figure 1

An overview of solid organ transplant rejection. The rejection of a solid organ transplant, such as the kidney depicted here, is initiated by migratory DCs of both donor and host origin. Donor DCs (red) are transplanted along with the graft itself, and upon their surgery-induced activation migrate to the draining LN via lymphatic vessels. These cells stimulate host T cells that react with graft-derived peptides presented by donor haplotype MHC molecules, a pathway termed “direct” allorecognition [41]. In contrast, host DCs (white) differentiate de novo within the graft from precursors recruited from host blood. Upon their subsequent migration to the LN, these cells stimulate host T cells that react with graft-derived peptides presented by host haplotype MHC molecules, a pathway termed “indirect” allorecognition. Both sets of activated T cells proliferate and differentiate within the LN to generate large numbers of effector T cells. These cells then exit the LN, migrate via the blood to the graft site, and then perform the effector functions that induce graft necrosis. These effector functions include the direct killing of graft cells by CD8⁺ cytotoxic T cells (CTLs) that possess direct alloreactivity to donor MHC class I molecules, as well as the elaboration of inflammatory cytokines such as IFN-γ and TNF-α by CD8⁺ and CD4⁺ T cells that possess either direct or indirect graft alloreactivity. These cytokines impair graft survival through a variety of mechanisms, including their direct killing of transplanted cells or host endothelial cells, or their activation of other effector cells of the immune system such as macrophages.

Figure 2

DC-mediated immune surveillance of the non-pregnant and pregnant uterus. (a) In the non-pregnant uterus, DCs are present within both the endometrium (orange cells) and the myometrium (blue cells). Even though the lymphatic vessels of the uterus are confined to the myometrium, maturing endometrial DCs reach these vessels by migrating through the ~0.2-0.4 mm that separates the uterine lumen from the myometrium [21]. This migration allows endometrial DCs to access the draining LN so they can presumably orchestrate immune responses to uterine pathogens. In contrast, the transformation of the endometrium into the decidua upon embryo implantation traps DCs the maternal/fetal interface (b), and thus prevents them from contributing towards T cell recognition of the fetus and placenta [21]. Fetal and placental antigens are instead only transported by DC-independent processes, to be presented by DCs already resident within the LN (and spleen). These latter cells tend to be less inherently immunogenic than DCs stationed within peripheral tissues. Most likely, DC migration from the maternal/fetal interface is severely limited because decidual DCs close to the placenta have to migrate through up to ~1-2 mm of interstitial tissue before encountering a lymphatic vessel. In contrast, myometrial DCs in both the pregnant and non-pregnant uterus have direct access to the myometrial lymphatics and can easily exit the uterus. The 1 mm scale bar applies to both the E8.5 implantation site cross-section as well as to the identically-scaled cross-section of the non-pregnant uterus. The lymphatic vessels of the uterus exit via the mesometrium, a membrane that runs longitudinally along its length. The E8.5 implantation site diagram also depicts the large number of dNK cells located towards the mesometrial pole of the decidua, as well as some major vascular structures.