There remain large gaps in our understanding of T cell homeostasis and its role in tissue specific tolerance. This application addresses these issues through the example of maternal immunity to antigens expressed on the fetus and placenta. Maternal tolerance of the fetus is thought to rely on several mechanisms, including limitation of cellular traffic across the maternal-fetal interface and suppression or deletion of fetal antigen specific T cells. However, others and we have shown that cellular traffic can occur between mother and fetus, and that immunity to fetal antigens can be generated during pregnancy. The result of such immunity is typically not one of fetal rejection, perhaps reflecting local (placental) factors that directly interfere with generated T cell effector function, or yet unknown factors that cause deletion of such cells. Nonetheless it is clear that these mechanisms can be broken. This proposal takes a broader view of tissue specific tolerance and suggests that while the rules for activation or inactivation of naive T cells are the same in pregnant and non pregnant mice, the homeostatic mechanisms governing the proliferation, trafficking and death of antigen experienced T cells may be unique in the pregnant host. It moreover suggests that regulation of these processes presents a reversible mechanism(s) by which the maternal immune system meets the two competing requirements of protection and tolerance of the fetus. In particular, this proposal seeks to examine tissue specific changes in maternal T cells, determine if these changes are antigen (particularly fetal/placental antigen) specific, and to evaluate whether prior exogenous (i.e. outside of pregnancy) exposure to antigen alters these effects. The experiments will utilize T cell receptor (TCR) transgenic mice specific for H-Y, (the antigen expressed on male cells of all mammals), allo-antigen, and experimentally expressed ovalbumin. Testing of the stated hypothesis may help explain the literature's conflicting data on whether the maternal immune system is suppressed. Such testing may also reveal novel mechanisms of tissue specific tolerance and immunity that can be used in the development of new strategies to treat recurrent miscarriage, autoimmune disease and sexually transmitted infections.
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