FETAL TROPHOBLASTS MAINTAIN MATERNAL TOLERANCE

有很强的选择压力来维持遗传多样性

There is a strong selective pressure to maintain genetic diversity in vertebrate populations. Central to this process is maintaining a state of tolerance between the mature, maternal immune system and the fetal "allograft". Because maternal tolerance is so critical, a number of overlapping mechanisms are undoubtedly important not only to prevent the initiation of an immunological response, but also to minimize th damage from any response that might inadvertently be initiated. Matgernal acceptance of the fetal "allograft" occurs without either general immunosuppression or even specific tolerance to paternal antigens. A pregnant female can reject tissue derived from the male partner without adverse effect on the developing fetus. Decades of work have suggested a number of both antigen-specific and antigen-independent models to explain this tissue-specific acceptance of the fetal allograft by the maternal immune system. In this proposal we will directly test two related, antigen-specific mechanisms that may contribute to tissue-specific tolerance of the developing fetus. The underlying framework of these experiments is that an understanding of the components necessary to break maternal tolerance and cause placental rejection will establish the relative importance of those components in maintaining tolerance in the native state. The hypothesis to be tested is that fetal trophoblast cells in contact with the maternal immune system provide protection by two mechanisms related to their capacity to present antigens to maternal T cells. We propose that under normal conditions fetal trophoblasts tail to effectively activate naive maternal T cells. If maternal T cells do become activated, we propose that the trophoblasts limit capacity for T cell expansion by triggering an antigen-dependent T cell death or deletion. The hypothesis will be tested by forcing the transgenic expression of target MHC antigens and or "co-stimulator" molecules. Expression will be controlled by promoters that regulate trophoblast- specific hormone expression. The role of the trophoblasts in triggering a pathway of antigen-dependent T cell death will be determined by using mutant strains of mice (lpr and gld) deficient in this pathway. These mice are prone to autoimmune disease and have mutations in the TNF receptor- and TNF-related proteins, fas and fas ligand, respectively. Successful completion of these experiments would provide the first direct evidence that either of these mechanisms is important in maintaining maternal tolerance to the fetus.