The immunological basis by which a

The immunological basis by which a mother tolerates her semi-allogeneic fetus remains poorly understood. Several mechanisms are likely to contribute to this phenomenon including active immune regulation by regulatory T cells. In this article, we report that human placental trophoblasts activate a clonal population of CD8+ T cells with regulatory function. These cells are not MHC class I restricted, but require costimulation through a member of the carcinoembryonic Ag family present on early gestation trophoblasts. These regulatory T cells express the mucosal markers CD101 and CD103 and display selective usage of the TCR gene Vβ9. CD8+ T cells isolated from the peripheral blood of pregnant mothers (16–28 wk) also demonstrate expansions in the same Vβ family (Vβ9), signaling a possible role for these cells in preventing fetal rejection in vivo. We have previously characterized a subset of CD8+ regulatory T cells activated by the combination of the nonclassical class I molecule CD1d and a costimulatory molecule of the carcinoembryonic Ag family present on the intestinal epithelium. These data support the concept that distinct regulatory T cell populations exist at different sites and may be regulated locally by unique restriction elements, costimulatory signals, and Ags.Allogeneic tissue grafts are typically rejected rapidly and require exogenous immunosuppressive medications to be tolerated. In contrast, the human fetus, which resembles a semi-allogeneic graft, is accepted by the maternal immune system in the majority of cases without intervention. Potential mechanisms underlying this phenomena are likely to be complex (1).Anatomically, placental trophoblasts occupy a unique position at the interface between mother and child. These epithelial cells possess several intriguing features that suggest a role for these cells in preventing fetal rejection. Trophoblasts express little or no classical MHC class I (HLA-A, -B, and -C) (2, 3, 4, 5), but do express a number of nonclassical MHC class I molecules. Examples include HLA-E (6) and HLA-G (7, 8), which can modulate the innate immune response and prevent NK (6) and NK T cell (9)-mediated cytotoxicity. Additionally, trophoblasts have been recently shown to express the nonclassical MHC class I molecule, CD1d, on the surface of first-trimester human trophoblasts (10).We have previously described a subset of CD8+ regulatory T cells in humans that is restricted by CD1d and a costimulatory molecule of the carcinoembryonic Ag (CEA)3 family expressed on intestinal epithelial cells (IEC). These cells use a restricted TCR repertoire (Vβ5.1/Vα18), are CD28−, and can suppress immune responses in vitro (11). In the intestine, these cells may play an important role in controlling inflammatory responses to normal commensal flora at the interface between the external environment and the mucosal immune system. Interestingly, patients with inflammatory bowel disease are deficient in the expression of the CEA subfamily costimulatory molecule, which correlates with an inability of these patients to be tolerized to orally administered Ags (12).