Activating T regulatory cells for tolerance in early pregnancy - the contribution of seminal fluid. J Reprod Immunol

Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, SA, Australia.
Journal of Reproductive Immunology (Impact Factor: 2.82). 10/2009; 83(1-2):109-16. DOI: 10.1016/j.jri.2009.08.003
Source: PubMed


A state of active tolerance mediated by T regulatory (Treg) cells must be functional from the time of embryo implantation to prevent the conceptus from maternal immune attack. Male seminal fluid and ovarian steroid hormones are implicated in regulating the size and suppressive function of the Treg cell pool during the peri-implantation phase of early pregnancy. Evidence that antigens and cytokine signals in seminal fluid regulate the maternal immune response includes the following: (1) the Treg cell-inducing cytokine TGFbeta and male alloantigens are present in seminal fluid; (2) seminal fluid delivery at coitus is sufficient to induce a state of active immune tolerance to paternal alloantigen, even in the absence of conceptus tissue; (3) female dendritic cells can cross-present seminal fluid antigens to activate both CD8(+) and CD4(+) T cells, and (4) mating events deficient in either sperm or seminal plasma result in diminished CD4(+) CD25(+) Foxp3(+) Treg cell populations at the time of embryo implantation. Ongoing studies indicate that the cytokine environment during priming to male seminal fluid antigens influences the phenotype of responding T cells, and impacts fetal survival in later gestation. Collectively, these observations implicate factors in the peri-conceptual environment of both male and female origin as important determinants of maternal immune tolerance. Defining the mechanisms controlling tolerance induction will be helpful for developing new therapies for immune-mediated pathologies of pregnancy such as miscarriage and pre-eclampsia.

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    • "For example, a Drosophila female's immunity to systemic infection drops after mating (Fedorka et al. 2007; Short and Lazzaro 2010; but see also Zhong et al. 2013) and upregulation of female immunity has been proposed to generate a hostile environment for sperm. That seminal fluid plays a role in mating related immunity is known in Drosophila, mice, and humans (Robertson et al. 2009; Guerin et al. 2009, 2011; Sharkey et al. 2012; Short et al. 2012), and seminal fluid of all animals tested to date includes predicted antimicrobial compounds (e.g., see Poiani 2006; Avila et al. 2011). "
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    ABSTRACT: Sexual reproduction requires coordinated contributions from both sexes to proceed efficiently. However, the reproductive strategies that the sexes adopt often have the potential to give rise to sexual conflict because they can result in divergent, sex-specific costs and benefits. These conflicts can occur at many levels, from molecular to behavioral. Here, we consider sexual conflict mediated through the actions of seminal fluid proteins. These proteins provide many excellent examples in which to trace the operation of sexual conflict from molecules through to behavior. Seminal fluid proteins are made by males and provided to females during mating. As agents that can modulate egg production at several steps, as well as reproductive behavior, sperm "management," and female feeding, activity, and longevity, the actions of seminal proteins are prime targets for sexual conflict. We review these actions in the context of sexual conflict. We discuss genomic signatures in seminal protein (and related) genes that are consistent with current or previous sexual conflict. Finally, we note promising areas for future study and highlight real-world practical situations that will benefit from understanding the nature of sexual conflicts mediated by seminal proteins. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 12/2014; 7(2). DOI:10.1101/cshperspect.a017533 · 8.68 Impact Factor
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    • "These molecules interact with cognate receptors on the epithelial lining of the female reproductive tract to initiate local cellular and molecular changes reminiscent of an inflammatory response [26]. These changes are required for maternal immune adaptation to pregnancy and for the generation of immune tolerance against fetal antigens [26,56]. However the molecular pathway by which seminal plasma mediates the expression of IL-1α and other cytokines is yet to be fully elucidated. "
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    ABSTRACT: Cervical cancer is a chronic inflammatory disease of multifactorial etiology usually presenting in sexually active women. Exposure of neoplastic cervical epithelial cells to seminal plasma (SP) has been shown to promote the growth of cancer cells in vitro and tumors in vivo by inducing the expression of inflammatory mediators including pro-inflammatory cytokines. IL-1alpha is a pleotropic pro-inflammatory cytokine induced in several human cancers and has been associated with virulent tumor phenotype and poorer prognosis. Here we investigated the expression of IL-1alpha in cervical cancer, the role of SP in the regulation of IL-1alpha in neoplastic cervical epithelial cells and the molecular mechanism underlying this regulation. Methods and results: Real-time quantitative RT-PCR confirmed the elevated expression of IL-1alpha mRNA in cervical squamous cell carcinoma and adenocarcinoma tissue explants, compared with normal cervix. Using immunohistochemistry, IL-1alpha was localized to the neoplastically transformed squamous, columnar and glandular epithelium in all cases of squamous cell carcinoma and adenocarcinomas explants studied. We found that SP induced the expression of IL-alpha in both normal and neoplastic cervical tissue explants. Employing HeLa (adenocarcinoma) cell line as a model system we identified PGE2 and EGF as possible ligands responsible for SP-mediated induction of IL-1alpha in these neoplastic cells. In addition, we showed that SP activates EP2/EGFR/PI3kinase-Akt signaling to induce IL-1alpha mRNA and protein expression. Furthermore, we demonstrate that in normal cervical tissue explants the induction of IL-1alpha by SP is via the activation of EP2/EGFR/PI3 kinase-Akt signaling. Conclusion SP-mediated induction of IL-1alpha in normal and neoplastic cervical epithelial cells suggests that SP may promote cervical inflammation as well as progression of cervical cancer in sexually active women.
    Journal of Molecular Signaling 08/2014; 9(1). DOI:10.1186/1750-2187-9-8
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    • "As pregnancy is established, embryo starts growing and the transfer of fetal cells, as well as cell debris into the maternal circulation increases (4). As for other antigens, paternal antigens can be up-taken by maternal professional antigen presenting cells (APCs), processed and presented to naïve T cell encouraging their differentiation into different T cell lineages, namely: Th1, Th2, Th17, or regulatory T cells depending on different signals (2, 5–7). "
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    ABSTRACT: DURING PREGNANCY, THE MATERNAL IMMUNE SYSTEM FACES A DOUBLE DILEMMA: tolerate the growing semi-allogeneic fetus and at the same time protect the mother and the progeny against pathogens. This requires a fine and extremely regulated equilibrium between immune activation and tolerance. As professional antigen presenting cells, B cells and in particular B-1a B cells, can activate or tolerize T cells and thus participate in the generation or regulation of the immune response. B-1a B cells were involved in the humoral immune response leading to pre-eclampsia, one of the main medical complications during pregnancy. Here we demonstrated that B-1a B cells are additionally involved in cellular immune mechanisms associated with pregnancy complications. Using a mouse model of pregnancy disturbances, we showed that B-1a B cells from animals suffering pregnancy disturbances but not from those developing normal pregnancies induce the differentiation of naïve T cells into Th17 and Th1 cells. This differential role of B-1a B cells during pregnancy seems to be associated with the co-stimulatory molecule CD86 as normal pregnant mice showed lower percentages of CD86 expressing B-1a B cells as compared to pregnant mice developing pregnancy disturbances or to non-pregnant animals. Our data bring to light a new and not explored role of B-1a B cells in the context of pregnancy.
    Frontiers in Immunology 01/2014; 5:6. DOI:10.3389/fimmu.2014.00006
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