During pregnancy the maternal immune system tolerates the persistence of fetal cells in maternal tissue. The fetus expresses maternal as well as paternal encoded molecules but is not rejected by the maternal immune system. The aim of this thesis was to determine whether maternal T cells contribute to fetus specific immune recognition and if mechanisms of fetus specific immune regulation exist in human pregnancy. A special emphasis is given to fetus specific immune recognition and immune regulation by maternal T cells at the fetal-maternal interface. In this thesis, we demonstrate that CD4+CD25bright regulatory T cells which are concentrated in decidual tissue have the capacity to down regulate fetus specific and 3rd party (non-specific) responses. In contrast, CD4+CD25bright T cells in maternal peripheral blood can regulate 3rd party (non-specific) responses, comparable to non-pregnant controls, while the capacity to regulate the fetus specific response is absent. These data suggest a preferential recruitment of fetus specific regulatory T cells from the peripheral blood to the fetal maternal interface. Analysis of the CD8+ T cell pool during pregnancy shows that decidual CD8+ T cells mainly consist of differentiated Effector-Memory T cells, while unprimed Na_ve cells are almost absent. Decidual Effector-Memory CD8+ T cells contain significantly reduced levels of the cytolytic molecule perforin. These data are suggestive for an alternative CD8+ T cell differentiation and regulation process that may play a crucial role in maintenance of maternal immune tolerance to the fetus. Database analysis of clinical pregnancy data, fetal-maternal HLA mismatches and decidual lymphocyte responses led to the conclusion that a fetal-maternal HLA-C mismatch is crucial for decidual CD4+ T cell activation and required for induction of functional CD4+CD25bright regulatory T cells in decidua. Hereby we provide the first evidence that decidual T cells specifically recognize a fetal HLA-C mismatch at the fetal-maternal interface, possibly using the indirect allorecognition pathway. However HLA-C recognition does not induce a destructive immune response in uncomplicated pregnancies. Besides TCR mediated allorecognition, low frequencies of decidual T cells express NK receptors that can specifically recognize HLA-C allotypes. Engagement of NK receptors on T cells can result in down regulation of TCR mediated T cell activation. Although, no experimental evidence is present so far, NK receptor expression on decidual T cells may provide an alternative way for decidual T cells to recognize allogeneic fetal cells and modulate the decidual immune response. In conclusion, this thesis shows that decidual T cells comprise a very heterogenic subset of T cells that include activated CD4+ and Effector-Memory type CD8+ T cells. However, these highly activated T cells are found together with T cell subsets that are capable to suppress the decidual lymphocyte response. Furthermore, we show that decidual T cells can specifically recognize a fetal-maternal HLA-C mismatch. Hereby we demonstrate that mechanisms of fetus specific allorecognition and T cell regulation are present at the fetal-maternal interface in uncomplicated human pregnancy. In summary our data show that the maternal T cells in the uterus recognize foreign fetal cells, however, due to the presence of immune suppressive regulatory T cells no detrimental immune reaction is induced. In future research it is important to translate our results to aberrant pregnancies where fetal growth retardation, maternal hypertension, pre-term birth or miscarriages may occur. Hereby, it is important to determine whether these immune suppressive regulatory T cells are present in the uterus, if they function properly and what factors (proteins or cells) attract or induce regulatory T cells at the fetal-maternal interface. Further unravelling of the mechanisms immune regulation during pregnancy may be crucial to understand why some pregnancies are successful whereas others are not.UBL - phd migration 201
