How the allogeneic fetus avoids maternal immune rejection during pregnancy is not only one of the outstanding questions in contemporary immunology, but is also now recognized to have major clinical relevance towards diseases such as recurrent spontaneous abortion and preeclampsia, as well as application towards organ transplantation. Although it is generally accepted that the maternal immune system is ?aware? that the fetus and placenta exist, studies to date have only focused on CD8+ T cells and B cells, and thus have not addressed the behavior of potentially reactive CD4+ T helper cells, the lymphocyte subset likely to play the most important role in any form of antigen-specific tolerance induction. Here, we will directly characterize the responses of both maternal CD4+ and CD8+ T cells towards a placentally expressed antigen, taking advantage of transgenic mice we have recently made that express the well-characterized model antigen ovalbumin in placental tissues (Aim 1). The use of this system will also allow us to test whether maternal tolerance towards the fetus and placenta is local or systemic, and whether it involves attenuation of affector or effector arms of the immune response. The nature of antigen presenting cells (APCs) in the pregnant uterus is another area that is virtually unexplored, despite the central role of these cells in regulating tolerance induction. Thus, we will characterize the behavior and antigen-presenting capacity of APCs in the pregnant uterus, focusing on resident dendritic cells, which have been completely uncharacterized in mice (Aim 2). Lastly, we describe the generation of novel transformed murine trophoblast cell lines directly from cultured trophoblast stem cells. Since these transformed trophoblasts are rejected in non-pregnant allogeneic mice following subcutaneous injection, they provide a powerful reagent for dissecting the relative importance of trophoblasts, the uterine environment, and the hormonal state of pregnancy in establishing maternal tolerance (Aim 3).
| Erlebacher, Adrian; Vencato, Daniela; Price, Kelly A et al. (2007) Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus. J Clin Invest 117:1399-411 |
| Erlebacher, Adrian; Zhang, Dorothy; Parlow, Albert F et al. (2004) Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system. J Clin Invest 114:39-48 |
| Erlebacher, Adrian; Price, Kelly A; Glimcher, Laurie H (2004) Maintenance of mouse trophoblast stem cell proliferation by TGF-beta/activin. Dev Biol 275:158-69 |
| Erlebacher, Adrian; Lukens, Amanda K; Glimcher, Laurie H (2002) Intrinsic susceptibility of mouse trophoblasts to natural killer cell-mediated attack in vivo. Proc Natl Acad Sci U S A 99:16940-5 |
