How the allogeneic fetus escapes rejection by the maternal immune system remains an outstanding question in transplantation immunology. One major assumption has been that trophoblasts, which are the placental cells directly in contact with maternal tissue, somehow attenuate the affector and/or effector arms of the maternal immune response and thus render themselves intrinsically resistant to immune attack. Here, we present two lines of evidence that directly contradict this assumption. First, we show that transformed mouse trophoblasts, which are akin to human choriocarcinoma cells, form tumours in immunodeficient mice yet are rejected in allogeneic immunocompetent mice. Second, we show that wild-type mouse trophoblasts are rapidly killed following intravenous injection into allogeneic mice. Using a panel of immunodeficient mouse strains, we show that, in both cases, the killing of ectopic trophoblasts requires host natural killer cells. The apparent intrinsic susceptibility of mouse trophoblasts to immune attack strongly suggests that it is the functional anatomy of the pregnant uterus, rather than an activity of trophoblasts themselves, that is of primary importance in preventing rejection of the fetus.
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