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Placental Fas Ligand Expression Is a Mechanism for Maternal Immune Tolerance to the Fetus¹

Departments of Obstetrics/Gynecology (S.W.K., N.H.) and Microbiology/Immunology (S.W.K., T.F.H., A.N.), Virginia Commonwealth University/Medical College of Virginia, Richmond, Virginia 23298

Address all correspondence and requests for reprints to: Dr. Scott Kauma, Departments of Obstetrics/Gynecology and Microbiology/Immunology, Virginia Commonwealth University/Medical College of Virginia, Box 980034, Richmond, Virginia 23298.

Fas ligand (FasL) is a peptide that plays an important immunoregulatory role in limiting the host immune response. Several studies have shown that the expression of FasL in the anterior chamber of the eye and the testis allows these tissues to be immunoprivileged sites. Immunotolerance is achieved by binding of FasL to its receptor (Fas) on activated immune cells, which results in cell apoptosis. To determine whether FasL has a role in maternal immune tolerance to the fetus, we looked for the expression of FasL in the human placenta. Immunoperoxidase staining localized FasL to both syncytiotrophoblast and cytotrophoblast in placental villi and chorionic extravillous trophoblast. Western analysis demonstrated FasL in placental villi and a human first-trimester trophoblast cell line (ED₂₇). In contrast, Fas was colocalized to CD45 (leukocyte common antigen) positive cells found in maternal decidua. When isolated peripheral blood lymphocytes were induced to express Fas with phytohemagglutinin (PHA) and interleukin-2 (IL-2) and then cocultured with trophoblast, 30% of the lymphocytes underwent apoptosis, as determined by the in situ death (TUNEL) assay. Neutralizing antibodies to FasL inhibited apoptosis by 40% in these studies. In contrast, activated lymphocytes cocultured with non-FasL-expressing fibroblasts or unactivated non-Fas-expressing lymphocytes cocultured with ED₂₇ trophoblast showed little evidence of apoptosis. These findings suggest that FasL expressed by fetal trophoblast cells can induce apoptosis in activated lymphocytes there by providing a mechanism for maternal immune tolerance to the fetus.

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