The hidden maternal-fetal interface: events involving the lymphoid organs in maternal-fetal tolerance

Abstract

The genetic disparity between the mother and fetus has long enticed immunologists to search for mechanisms of maternal tolerance to fetal antigens. The study of antigen-specific tolerance in murine and human pregnancy has gained new momentum in recent years through the focus on antigen-presenting cells, uterine lymphatics and fetal antigen-specific maternal T cell responses. In mice, we now know that these responses occur within the secondary lymphoid structures as they can be conveniently tracked through the use of defined, often transgenic fetal antigens and maternal T cell receptors. Although the secondary lymphoid organs are sites of both immunization and tolerization to antigens, the immunological processes that occur in response to fetal antigens during the healthy pregnancy must invariably lead to tolerance. The molecular properties of these maternal-fetal tolerogenic interactions are still being unraveled, and are likely to be greatly influenced by tissue-specific microenvironments and the hormonal milieu of pregnancy. In this article, we discuss the events leading to antigen-specific maternal tolerance, including the trafficking of fetal antigens to secondary lymphoid organs, the properties of the antigen-presenting cells that display them to maternal T lymphocytes, and the nature of the ensuing tolerogenic response. Experimental data generated from human biological specimens as well as murine transgenic models are considered.

Fig. 1. Role of maternal dendritic cells in the induction of fetal tolerance

Fetal antigens released from trophoblast cells as a consequence of apoptotic cell death (A) or by shedding of syncytiotrohpoblast debris (C) traffic into the mother, where they may be taken up and displayed by maternal dendritic cells (DC) within the uterus, spleen or lymph node (A,B,D). Apoptotic debris or cells program the dendritic cells to take on a tolerogenic phenotype. Peripheral T cell tolerance would subsequently be induced through apoptosis, anergy, or conversion to T_R cells (E).