Fetus specific immune recognition and regulation by T cells at the fetal-maternal inferface in human pregnancy

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

Emerging role of C5aR2: novel insights into the regulation of uterine immune cells during pregnancy

Pregnancy is a fascinating immunological phenomenon because it allows allogeneic fetal and placental tissues to survive inside the mother. As a component of innate immunity with high inflammatory potential, the complement system must be tightly regulated during pregnancy. Dysregulation of the complement system plays a role in pregnancy complications including pre-eclampsia and intrauterine growth restriction. Complement components are also used as biomarkers for pregnancy complications. However, the mechanisms of detrimental role of complement in pregnancy is poorly understood. C5a is the most potent anaphylatoxin and generates multiple immune reactions via two transmembrane receptors, C5aR1 and C5aR2. C5aR1 is pro-inflammatory, but the role of C5aR2 remains largely elusive. Interestingly, murine NK cells have been shown to express C5aR2 without the usual co-expression of C5aR1. Furthermore, C5aR2 appears to regulate IFN-γ production by NK cells in vitro. As IFN-γ produced by uterine NK cells is one of the major factors for the successful development of a vital pregnancy, we investigated the role anaphylatoxin C5a and its receptors in the establishment of pregnancy and the regulation of uterine NK cells by examinations of murine C5ar2–/– pregnancies and human placental samples. C5ar2–/– mice have significantly reduced numbers of implantation sites and a maternal C5aR2 deficiency results in increased IL-12, IL-18 and IFN-γ mRNA expression as well as reduced uNK cell infiltration at the maternal-fetal interface. Human decidual leukocytes have similar C5a receptor expression patterns showing clinical relevance. In conclusion, this study identifies C5aR2 as a key contributor to dNK infiltration and pregnancy success

Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance

A fetus is inherently antigenic to its mother and yet is not rejected. The T regulatory (Treg) subset of CD4^+ T cells can limit immune responses and has been implicated in maternal tolerance of the fetus. Using virgin inbred mice undergoing a first syngenic pregnancy, in which only the male fetuses are antigenic, we demonstrate a maternal splenocyte proliferative response to the CD4^+ T cell restricted epitope of the male antigen (H-Y) in proportion to the fetal antigen load. A portion of the maternal immune response to fetal antigens is Treg in nature. The bystander suppressive function of pregnancy-generated Tregs requires the presence of the fetal antigen, demonstrating their inherent antigen specificity. In vivo targeting of diphtheria toxin to kill Tregs leads to a lower fraction of live male offspring and a selective reduction in mass of the surviving males. Thus, Tregs generated in the context of pregnancy function in an antigen-specific manner to limit the maternal immune response to the fetus in a successful pregnancy

До 60-річчя Андрія Вікторовича Мокієнко

Stemcel biology/Regenerative medicine (incl. bloodtransfusion

Marktonderzoek Private Lease

De hoofdvraag luidt: ‘Welke aspecten kenmerken de markt van private lease?’ Dezevraag is door het Ministerie van Financiën verbijzonderd in de vier deelvragen:1. Hoe is private lease (wettelijk) geregeld?2. Hoe ziet de aanbodzijde van de markt van private lease eruit?3. Hoe ziet de vraagkant van de markt van private lease eruit?4. Hoe verhoudt private lease zich tot de schuldenproblematiek