The fetus and its placenta, collectively called the conceptus, are semi-allogeneic to the mother, as they express transplantation antigens of paternal origin. Foreign tissues generally experience immunological rejection by the host immune system; however in a normal healthy pregnancy the conceptus does not undergo immune attack. Emerging evidence indicates the conceptus avoids rejection through a number of mechanisms including the induction of active maternal immune tolerance specific for paternal antigens. However, the mechanisms responsible for establishing this tolerance remain undefined, including the timing of the first encounter with paternal antigen and the cellular processes by which paternal antigen is presented to the maternal immune system. Exposure to paternal transplantation antigens occurs in two waves: initially in the context of male seminal fluid at conception, and secondly after placental trophoblast invasion of maternal tissues in mid-gestation pregnancy. Therefore the aim of this research was to evaluate the female immune response to paternal antigens in seminal fluid and those associated with the conceptus. The mechanisms of antigen presentation, the impact of the cytokine environment and the consequences of T cell activation on pregnancy were also investigated. A transgenic system using ovalbumin (OVA) as the model paternal antigen was established. The transgenic Act-mOVA mouse expresses OVA constitutively and ubiquitously under a B-actin promoter and OVA was shown to be present in seminal fluid and in the fetal and placental tissue of sired progeny. The OVA-reactive CD8+ OT-I and CD4+ OT-II T cells were employed to gauge the relative amount of OVA antigen presented, with the strength of the maternal immune response quantified based upon the extent of T cell proliferation, as assessed by CFSE dye-dilution. Utilising bone marrow chimeric mice, it was demonstrated that upon insemination by an Act-mOVA male, seminal fluid-derived OVA was processed and indirectly presented by maternal bone marrow-derived antigen presenting cells to induce activation and proliferation of the CD8+ OT-I T cells within the uterinedraining para-aortic lymph nodes of the female. Likewise, OT-II T cells were responsive to MHC class II-restricted presentation of seminal fluid OVA. Post-implantation conceptus-derived OVA was detected within peripheral lymph nodes and the spleen where it was presented via the MHC class I and class II-restricted pathways to induce systemic proliferation of both OT-I and OT-II T cells. Furthermore, as gestation advanced the extent of OVA presentation and hence T cell proliferation intensified. Conceptus-derived OVA was still presented systemically until 20 days pp. The impact of the uterine cytokine environment was assessed to determine its influence on seminal OVA antigen processing and presentation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a key factor in regulating the leukocyte population of the female reproductive tract. GM-CSF-deficient female mice were unable to process and present seminal fluid OVA as effectively or efficiently as their wildtype counterparts, as assessed by their reduced capacity to drive OT-I and OT-II T cell proliferation following insemination by an Act-mOVA male. Finally, with highly-reactive OVA-specific T cells activated in response to seminal and conceptus OVA antigen, it was of interest to determine the effect of OT-I T cell activation on fetal survival and pregnancy success. It was found that OT-I T cells activated in vivo to paternal OVA antigen in the context of seminal fluid and pregnancy were not deleterious to pregnancy outcomes. However the transfer of cytotoxic OT-I T cells generated in vitro in the presence of an IL-2 into female mice carrying OVA-expressing conceptuses was detrimental to fetal survival. Collectively these experiments demonstrated that the initial exposure to paternal antigen, and hence the first opportunity to develop paternal antigen-specific tolerance, occurs at insemination. Paternal antigen is presented to the maternal T cell repertoire throughout gestation and may play a role in maintaining immune tolerance during pregnancy. The processing and presentation of paternal-derived antigen is chiefly performed by female bone marrow-derived antigen presenting cells. The cytokine environment of the mated female reproductive tract is critical in allowing optimal antigen processing and presentation, to generate an immune response consistent with maternal immune tolerance of the conceptus. / Thesis (Ph.D.) - University of Adelaide, School of Paediatrics and Reproductive Health, 2008
| Identifer | oai:union.ndltd.org:ADTP/264604 |
| Date | January 2008 |
| Creators | Moldenhauer, Lachlan |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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