UCSF

The semi-allogeneic fetus derives half of its genetic maternal from the mother. The other half, inherited from the father, leads to the expression of proteins that are foreign to the mother. In danger of potential immune recognition and rejection, the fetus is dependent on maternal immune regulation. Multiple mechanisms are in place to ensure the mother and fetus live in harmony during pregnancy, as outlined in Chapter one. This dissertation discusses what happens to some of these mechanisms during fetal intervention in mice.

Chapter two focuses on T cell specific mechanisms that prevent maternal T cell activation during pregnancy. These mechanisms include constraint in antigen presentation to maternal T cells, deletion of maternal T cells aware of fetal antigens and the lack of recruitment of maternal T cells to the uterine environment. Fetal intervention in mice results in enhanced antigen presentation with a reduction in apoptosis of activated cells and a more prominent presence of maternal T cells in the uterus. Maternal T cells also play a role in fetal demise (preterm labor) during fetal intervention.

Chapter three discusses changes in trafficking maternal cells during fetal intervention. Trafficking of maternal cells into fetal blood during normal pregnancy encourages generation of fetal Tregs that can suppress an anti-maternal T cell response. During fetal intervention, the presence of maternal T cells, maternal microchimerism (MMc), increases and may play a role in limiting engraftment of cells transplanted in utero. Because fetal intervention results in preterm labor, changes in maternal microchimerism during fetal intervention may also play a role in mediating fetal rejection during preterm labor. Using a mouse model of preterm labor, we saw enhanced maternal microchimerism in fetal blood. The contribution of maternal cells in fetal blood to the pathogenesis of preterm labor is an open field for further investigation.

Chapter four deals with the role of maternal Tregs in regulating maternal immune responses during fetal intervention. This chapter more specifically examines maternal antibody production against "conceptus-derived" antigens in the absence of Tregs during normal pregnancy and fetal intervention. Tregs prevent production of maternal antibodies during pregnancy. During fetal intervention, however, maternal antibody production does not increase, even in the absence of Tregs. The presence of "conceptus-derived" antigens in maternal circulation may play a role in preventing detection of maternal antibodies during fetal intervention. Because maternal antibodies do not have an effect on the success of pregnancy, alternative mechanisms may play a role in protecting pregnancy.

This dissertation discusses how the regulatory mechanisms protecting the semi-allogeneic fetus during pregnancy are disrupted during fetal intervention and may play a role in preterm labor. The results discussed in this dissertation provide support for a novel role of the maternal adaptive immune system in the rejection of the fetus during pregnancy complications. Finally, Chapter five discusses the future directions that have come about because of this thesis work.