UVM Theses and Dissertations
Format:
Print
Author:
Norton, Michelle Shepard
Dept./Program:
Cell and Molecular Biology Program
Year:
2010
Degree:
Ph. D.
Abstract:
Classical immunology states that lymphocytes recognize pathogens because they express molecules that are foreign to the host. This discrimination begins during early development, in which cells that respond robustly to host-derived proteins are deleted. In this model, pregnancy represents an immunological paradox because the fetus expresses paternally encoded proteins that should be recognized by maternal lymphocytes as foreign, and yet it is normally not rejected. The tolerance of the semi-allogeneic fetus during pregnancy led to the generation of multiple theories of maternal immune suppression. However, during pregnancy the activity of cytotoxic CD8 T cells is required to protect the mother and fetus from infections. At the same time robust activation of anti-fetal CD8 T cells could lead to the generation of a detrimental immune response at the maternal-fetal interface. Therefore, these lymphocytes must be regulated in order to preserve responsiveness to pathogens while maintaining fetal tolerance.
Pregnancy induces changes in multiple organs throughout the body, including the immune system. There is a reversible increase in the size of the spleen and uterine draining lymph nodes during gestation. In contrast the size and cellularity of the thymus decreases during pregnancy and returns to normal after parturition. Because the effect of pregnancy on systemic immune cell homeostasis was unclear, we used a normal mouse model to characterize the changes in the cellularity of the spleen throughout gestation. There was a significant expansion of the splenic erythroid precursor population in early and mid-pregnancy that was facilitated by impressive levels of proliferation. This led to decreased proportions of both T and B lymphocytes in the spleen, however the proliferative capacity of these cells was retained.
We further went on to characterize the specific effects of pregnancy on maternal CD8 T cells, both systemically in the spleen and locally in the uterine draining lymph nodes. In both tissues there was no decrease in the absolute number of CD8 T cells during pregnancy and depending on the day of gestation the proliferation of these cells was either equivalent to or higher than cells isolated from unmated controls. We then used T cell receptor transgenic mice to determine the capacity of CD8 T cells to kill target cells in vivo during pregnancy. We found that anti-HY CD8 T cells in Matahari mice retained the ability to specifically kill injected male cells, with no adverse effects on male fetuses despite the presence of large numbers of these cells at the maternal-fetal interface.
Overall we have found that cytotoxic CD8 T cells retain their proliferative capacity and cytolytic activity during pregnancy and are not excluded from the maternal-fetal interface. These data do not support a model of global T cell suppression during pregnancy, and suggest that tissue specific regulation may be important for balancing systemic immunity and fetal tolerance.
Pregnancy induces changes in multiple organs throughout the body, including the immune system. There is a reversible increase in the size of the spleen and uterine draining lymph nodes during gestation. In contrast the size and cellularity of the thymus decreases during pregnancy and returns to normal after parturition. Because the effect of pregnancy on systemic immune cell homeostasis was unclear, we used a normal mouse model to characterize the changes in the cellularity of the spleen throughout gestation. There was a significant expansion of the splenic erythroid precursor population in early and mid-pregnancy that was facilitated by impressive levels of proliferation. This led to decreased proportions of both T and B lymphocytes in the spleen, however the proliferative capacity of these cells was retained.
We further went on to characterize the specific effects of pregnancy on maternal CD8 T cells, both systemically in the spleen and locally in the uterine draining lymph nodes. In both tissues there was no decrease in the absolute number of CD8 T cells during pregnancy and depending on the day of gestation the proliferation of these cells was either equivalent to or higher than cells isolated from unmated controls. We then used T cell receptor transgenic mice to determine the capacity of CD8 T cells to kill target cells in vivo during pregnancy. We found that anti-HY CD8 T cells in Matahari mice retained the ability to specifically kill injected male cells, with no adverse effects on male fetuses despite the presence of large numbers of these cells at the maternal-fetal interface.
Overall we have found that cytotoxic CD8 T cells retain their proliferative capacity and cytolytic activity during pregnancy and are not excluded from the maternal-fetal interface. These data do not support a model of global T cell suppression during pregnancy, and suggest that tissue specific regulation may be important for balancing systemic immunity and fetal tolerance.