Journal

JOURNAL IMMUNOLOGY

BRIEF REVIEWS Maternal Acceptance of the Fetus: True Human Tolerance
Indira Guleria1 and Mohamed H. Sayegh
Induction and maintenance of immunologic tolerance in humans remains a desirable but elusive goal. Therefore, understanding the physiologic mechanisms of regulation of immune responses is highly clinically relevant for immune-mediated diseases (e.g., autoimmunity andasthma/ allergy) and for cell and organ transplantation. Acceptance of the fetus, which expresses paternally inherited alloantigens, by the mother during pregnancy is a unique example of how the immune system reshapes a destructive alloimmune response to a state of tolerance. Understanding the complex mechanisms of fetomaternal tolerance has important implications for developing novel strategiesto induce immunologic tolerance in humans in general and for prevention of spontaneous abortion in at-risk populations in particular. The Journal of Immunology, 2007, 178: 3345–3351.
cidual cells) that play a role in fetomaternal tolerance. Mouse and human placentas are both composed of layers of cells with distinct functions (5). The outer layer of the mouse placenta, which mediates implantationand invasion into the uterus, is composed of trophoblast giant cells. The layer with analogous function in humans is composed of invasive extravillous cytotrophoblast cells (6, 7). The function of the middle layer of the mouse placenta, the spongiotrophoblast, is largely unknown. However, some of the spongiotrophoblast cells can differentiate into trophoblast giant cells resembling thecytotrophoblast cell columns that anchor the villi of the human placenta (5). The labyrinth layer of the mouse placenta is comparable in function to the chorionic villi of the human placenta. In both the mouse and human placentas, the labyrinthine and villi, respectively, are covered by syncytiotrophoblasts that lie in direct contact with maternal blood.
Mechanisms of fetomaternal tolerance

T

he fetusrepresents a foreign entity to the maternal immune system, yet this “natural” allograft is not normally rejected. Fifty years ago, Medawar (1) proposed that immunological tolerance should be present during pregnancy to protect against an aggressive maternal alloimmune response directed at the paternal Ags expressed by the fetus. Recurrent pregnancy loss affects 1–3% of all couples, and about halfof these cases have no identifiable cause (2). Furthermore, a number of studies associate some pregnancy complications with abnormal maternal immune responses (3, 4). Our understanding of tolerance mechanisms enabling a state of pregnancy is at this stage far from complete. In this review, we will highlight the known mechanisms of fetomaternal tolerance with particular emphasis on recentdevelopments and future directions in the field.

Many mechanisms protect the fetus from the maternal immune system. These include the expression of nonclassical MHC molecules by trophoblast cells (8, 9), tryptophan catabolism by the enzyme IDO (10), T cell apoptosis (11), and the complement system (12, 13). Recent studies have also documented a role for regulatory T cells (Tregs) (14 –17). Finally, wehave demonstrated a role for the inhibitory costimulatory molecule, programmed death ligand (PDL)1, in maintenance of fetomaternal tolerance (18). Fig. 1 depicts all of the relevant players (molecules and cell types) that have been shown to play a role in fetomaternal tolerance and their location in the placenta.
Role of MHC Lack of MHC molecules on trophoblast. Most of the polymorphic MHC classIa Ags are lacking on the surface of fetally derived trophoblast cells in both mice and humans with some exceptions as cited below (19). In the mouse, some polymorphic fetal MHC class I Ags have been reported on interstitial trophoblasts, mostly in the maternal decidua basalis, but not on endovascular trophoblasts (20). MHC class II Ags are also absent on trophoblast cells (21). The absence of...