FUNCTIONAL COOPERATION BETWEEN TROPHOBLAST HLA-G AND B7 FAMILY

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ABSTRACT-PROJECT 11 Background. Stimulation of lymphocytes requires the delivery of two cooperating signals provided by antigen presenting cells. The first signal is provided by human leukocyte antigens (HLA), while the second is provided by a member of the B7 family of costimulatory molecules. Unlike classical antigen presenting cells, however, trophoblast cells possess a distinctive combination of both classes of molecules. Specifically, trophoblast cells constitutively express non-classical HLA-G molecules as well as the newly discovered B7 family member, B7- H1. In vitro and in vivo studies have shown that expression of the B7 and HLA proteins can inhibit leukocyte activation and alter cytokine secretion, and that aberrant expression of these proteins can contribute to conditions such as cancer and autoimmune disease. Our preliminary data show that trophoblast-associated Hl_A-G and B7-H1 also inhibits production of the proinflammatory cytokine interferon-y by T cells, suggesting that trophoblast cells use these molecules for protection of the fetal semiallograft. We and others have also demonstrated that oxygen and proinflammatory cytokines, which are associated with preeclampsia and preterm delivery, alter expression of trophoblast-associated B7-H1 and HLA-G. Thus, altered expression of trophoblast HLA and B7s precipitated by abnormal oxygen and/or cytokine conditions in the placenta could lead to the reduced or enhanced ability of trophoblast cells to inhibit maternal leukocytes. Specific goals. The findings of the expression of unique members of the HLA and B7 families by trophoblast cells raises the question of whether these molecules functionally cooperate to deliver signals to lymphocytes in a manner similar to classical members of these families. The Specific Aims of Project II are to 1) determine the relative levels of expression of members of HLA-G and B7-H1 in normal and pathologic pregnancies; 2) determine whether the presence of trophoblast B7-H1 influences the effects of trophoblast HLA-G on maternal T lymphocytes; 3) examine whether B7-H1 influences antigen presentation activity of HLA-G1-expressing trophoblast cell lines. In Aim 1, tissue and purified trophoblast cells from placentas of normal, preeclamptic, and preterm pregnancies will be examined by molecular, histological, and flow cytometric techniques to determine whether the balance of these proteins is offset in compromised pregnancies. In Aim 2, we will perform functional assays to compare the ability of HLA and B7 family molecules, alone and in combination, to regulate leukocyte function. Finally, Aim 3 is designed to determine whether trophoblast-associated HLA-G can provide anti-viral protection at the maternal-fetal interface. Here, we will test whether HLA-G can present viral peptides to T cells, and whether the presence of B7-H1 affects its ability to do so.