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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Hewitt, Tyl
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University of Vermont & St Agric College
Obstetrics & Gynecology
Schools of Medicine
United States
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Bonney, Elizabeth A (2016) Immune Regulation in Pregnancy: A Matter of Perspective? Obstet Gynecol Clin North Am 43:679-698
PrabhuDas, Mercy; Bonney, Elizabeth; Caron, Kathleen et al. (2015) Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat Immunol 16:328-34
Bonney, Elizabeth A; Brown, Stephen A (2014) To drive or be driven: the path of a mouse model of recurrent pregnancy loss. Reproduction 147:R153-67
Shepard, Michelle T; Bonney, Elizabeth A (2013) PD-1 regulates T cell proliferation in a tissue and subset-specific manner during normal mouse pregnancy. Immunol Invest 42:385-408
Brown, Lucia Y; Bonney, Elizabeth A; Raj, Renju S et al. (2013) Generalized disturbance of DNA methylation in the uterine decidua in the CBA/J x DBA/2 mouse model of pregnancy failure. Biol Reprod 89:120
Bonney, Elizabeth A (2013) Demystifying animal models of adverse pregnancy outcomes: touching bench and bedside. Am J Reprod Immunol 69:567-84
Rincon, Mercedes R; Oppenheimer, Karen; Bonney, Elizabeth A (2012) Selective accumulation of Th2-skewing immature erythroid cells in developing neonatal mouse spleen. Int J Biol Sci 8:719-30
Bonney, Elizabeth A; Shepard, Michelle T; Bizargity, Peyman (2011) Transient modification within a pool of CD4 T cells in the maternal spleen. Immunology 134:270-80
Norton, Michelle T; Fortner, Karen A; Oppenheimer, Karen H et al. (2010) Evidence that CD8 T-cell homeostasis and function remain intact during murine pregnancy. Immunology 131:426-37
Bizargity, Peyman; Bonney, Elizabeth A (2009) Dendritic cells: a family portrait at mid-gestation. Immunology 126:565-78

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