Discovery Provides Insight into Fundamental Mystery of Fetal-Maternal Immune Tolerance

Scientists for the first time have discovered key steps in the molecular mechanisms involved in preventing the immune system of pregnant mammals from rejecting fetal tissue as foreign. The findings may also provide leads to better understanding and treatment of medical conditions arising from abnormalities in this and similar immune system pathways.

Although the foreign antigens of the developing fetus and of the placenta come into direct contact with cells of the maternal immune system, they fail to evoke the typical rejection response seen with organ transplant tissue and pathogens. Previous findings by researchers at New York University School of Medicine (New York City, NY, USA) prompted them to ask if there was some sort of barrier preventing activated T cells from reaching the fetus. They turned their attention to studying properties of the decidua and there, in a mouse model, they found new answers. The research team has now discovered that the onset of pregnancy causes the genes responsible for recruiting immune cells to sites of inflammation to be turned off within the decidua. As a result, T cells are not able to accumulate inside the decidua and therefore do not attack the fetus and placenta. Specifically, the implantation of an embryo changes the packaging of certain chemokine genes in the nuclei of the developing decidua's stromal cells. The change in the DNA packaging permanently silences (deactivates) the chemokine genes. Consequently, the chemokines are not expressed and T cells are not recruited to the site of embryo implantation.

Also of note, the observed change in the DNA packaging occurred by epigenetic modification, a modification that changes gene expression but not due to a hereditable gene mutation. So the findings also reveal “epigenetic modification of chemokine genes within tissue stromal cells as a modality for limiting the trafficking of activated T cells," said lead investigator Adrian Erlebacher, MD, PhD, associate professor of pathology at NYU School of Medicine and member of the NYU Cancer Institute at NYU Langone Medical Center. "It turns out that the cells that typically secrete the chemoattractants to bring the T cells to sites of inflammation are inhibited from doing so in the context of the pregnant uterus. The decidua appears instead as a zone of relative immunological inactivity," he explained.

Prof. Erlebacher and his team will next investigate whether these modifications are also present within the human decidua and whether the failure to generate them appropriately is associated with complications of human pregnancy. In addition to pregnancy, the study’s findings could also have medical implications for organ transplantation, autoimmune diseases, and even cancer since they also raise the possibility that the same kind of mechanism could enhance a tumor's ability to survive inside its host.

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New York University School of Medicine