. Pregnancy is an intricately orchestrated process where expanded tolerance to ?non-self? antigens expressed by the developing fetus and host defense against infection are each simultaneously maintained. Reciprocally, catastrophic complications arise when either host defense or tolerance to the fetus is disrupted. A number of human pathogens that includes Listeria, Plasmodium, E. coli, Group B Streptococcus, Salmonella, Chlamydia and cytomegalovirus each have a defined predisposition for prenatal infection that often results in spontaneous abortion or stillbirth. Therefore, unraveling the immune defects that cause these naturally occurring ?holes? in host defense during pregnancy has direct implications for new therapies aimed at boosting immunity against prenatal infection. We have assembled a novel set of transgenic mouse tools that allow the natural heterogeneity between maternal and fetal antigen to be recapitulated, and the precise identification of maternal immune cells with fetal specificity each during pregnancy. Our overall hypothesis is that the physiological expansion of immune suppressive maternal regulatory T cells (Tregs) required for sustaining tolerance to the developing fetus compromises host defense against pathogens that cause prenatal infection. This is based on our recently published initial studies establishing susceptibility to prenatal Listeria infection is dictated by expanded maternal Tregs. Therefore, with the newfound heterogeneity and functional specialization among regulatory T cells that use unique cell-intrinsic molecules to mediate context specific immune suppression, our first goals are to identify the maternal Treg intrinsic molecules that compromise host defense and dissociate these from other cell intrinsic molecules required for sustaining fetal tolerance during pregnancy. On the other hand, the immune response to infection also has built in ways to override the impacts of Treg suppression that stimulate immune activation and optimal host defense against infection. During pregnancy however, these transient reductions in maternal Treg suppression also fracture tolerance to the developing that can dictate fetal injury or resorption. Accordingly, our secondary goals are to investigate how prenatal infection impacts maternal Treg-mediated fetal tolerance. The first two aims will build upon a productive line of investigation illustrated in our recent publications and initial studies using prenatal Listeria infection to dissect the molecular basis for how maternal Tregs cause infection susceptibility, and to identify the Listeria-specific virulence determinants required for overriding maternal Treg suppression. To establish the broader applicability of these findings, the final aim will investigate if overriding maternal Treg-mediated fetal tolerance also occurs for other pathogens that cause prenatal infection (e.g. Plasmodium, E. coli, Group B Streptococcus, Salmonella, Chlamydia, and cytomegalovirus). The completion of these experiments will unravel how maternal Tregs cause prenatal infection susceptibility, and establish how infection-induced shifts in Treg-mediated fetal tolerance dictates injury to the developing fetus during prenatal infection.
The immune basis for why pregnancy confers infection susceptibility and the pathogenesis of fetal injury during prenatal infection will each be investigated. These results have important implications for designing improved therapies for the prevention and treatment of prenatal infection.
|Jiang, T T; Chaturvedi, V; Ertelt, J M et al. (2015) Commensal enteric bacteria lipopolysaccharide impairs host defense against disseminated Candida albicans fungal infection. Mucosal Immunol 8:886-95|
|Xin, Lijun; Ertelt, James M; Rowe, Jared H et al. (2014) Cutting edge: committed Th1 CD4+ T cell differentiation blocks pregnancy-induced Foxp3 expression with antigen-specific fetal loss. J Immunol 192:2970-4|
|Kinder, Jeremy M; Jiang, Tony T; Clark, Dayna R et al. (2014) Pregnancy-induced maternal regulatory T cells, bona fide memory or maintenance by antigenic reminder from fetal cell microchimerism? Chimerism 5:16-9|
|Jiang, Tony T; Chaturvedi, Vandana; Ertelt, James M et al. (2014) Regulatory T cells: new keys for further unlocking the enigma of fetal tolerance and pregnancy complications. J Immunol 192:4949-56|
|Xin, Lijun; Jiang, Tony T; Chaturvedi, Vandana et al. (2014) Commensal microbes drive intestinal inflammation by IL-17-producing CD4+ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2. Proc Natl Acad Sci U S A 111:10672-7|
|Clark, Dayna R; Chaturvedi, Vandana; Kinder, Jeremy M et al. (2014) Perinatal Listeria monocytogenes susceptibility despite preconceptual priming and maintenance of pathogen-specific CD8(+) T cells during pregnancy. Cell Mol Immunol 11:595-605|
|Ertelt, James M; Buyukbasaran, Esra Z; Jiang, Tony T et al. (2013) B7-1/B7-2 blockade overrides the activation of protective CD8 T cells stimulated in the absence of Foxp3+ regulatory T cells. J Leukoc Biol 94:367-76|
|Rowe, Jared H; Ertelt, James M; Xin, Lijun et al. (2013) Regulatory T cells and the immune pathogenesis of prenatal infection. Reproduction 146:R191-203|
|Tubo, Noah J; Pagan, Antonio J; Taylor, Justin J et al. (2013) Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell 153:785-96|
|Elahi, Shokrollah; Ertelt, James M; Kinder, Jeremy M et al. (2013) Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 504:158-62|