The primate placenta is unique in its selective expression of nonclassical MHC class I molecules (in the human HLA-G and HLA- E). Recent work has strongly suggested that HLA-E may play an important role in its coexpression with HLA-G on human trophoblasts in establishing maternal-fetal immune tolerance. However, the functional relevance of the unusual expression of MHC molecules in the human placenta remains undefined. A lack of appropriate nonprimate animal models has significantly restrained progress in this area. Our central hypothesis is that nonclassical placental MHC class I molecules play a role in the modulation of the maternal response to pregnancy, both locally within the maternal endometrium as well as in the maternal peripheral serum. To functionally address the role(s) of MHC class I molecule expression in the placenta, we propose 4 specific aims, using a nonhuman primate model for maternal-fetal immune tolerance developed in the previous funding period. Specific Aim 1. To define the ontogeny of Mamu-E expression within the rhesus placenta and localize sites of mRNA and protein expression. Specific Aim 2. To evaluate maternal-fetal immune interactions and placental development in pregnancies with transgenic modification of rhesus placental MHC class I expression. Specific Aim 3. To determine MHC class I expression in rhesus monkey trophoblasts exposed to simian cytomegalovirus, with relevance for maternal-fetal viral transmission. Specific Aim 4. To define the expression of a soluble isoform of Mamu-AG. Although there has been remarkable progress in defining the biochemical and molecular characteristics of MHC class I molecules expressed in the human placenta, a significant gap remains in our appreciation of either the function of these molecules in normal pregnancy, or the role(s) they may play in pathological situations. With these 4 specific aims we proceed beyond defining placental nonclassical MHC class I expression in the nonhuman primate, to investigating function at the maternal-fetal interface. The successful implementation of our recent adaptation of transgenic technology to the primate placenta will provide unprecedented opportunity for novel models of primate placental biology.