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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    • "However, not all APCs are tolerogenic as the immune environment at this stage of pregnancy is highly varied with both tolerogenic and immunogenic cells present, demonstrating differing roles for these cells during peri-conception (Jaiswal et al. 2012 ). The APCs are thought to take up paternal antigens and either traffi c to the uterine draining lymph nodes or interact locally with resident uterine T cells driving activation and expansion of clonal subsets of Treg cells which recognise and appropriately respond to paternal/fetal antigens (Robertson et al. 2009a ). An antigen-specifi c T cell response has been demonstrated using a T cell receptor transgenic model with OVA as a model paternal antigen (Moldenhauer et al. 2009 ). "
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    ABSTRACT: Carriage of sperm is not the only function of seminal fluid in mammals. Studies in mice show that at conception, seminal fluid interacts with the female reproductive tract to induce responses which influence whether or not pregnancy will occur, and to set in train effects that help shape subsequent fetal development. In particular, seminal fluid initiates female immune adaptation processes required to tolerate male transplantation antigens present in seminal fluid and inherited by the conceptus. A tolerogenic immune environment to facilitate pregnancy depends on regulatory T cells (Treg cells), which recognise male antigens and function to suppress inflammation and immune rejection responses. The female response to seminal fluid stimulates the generation of Treg cells that protect the conceptus from inflammatory damage, to support implantation and placental development. Seminal fluid also elicits molecular and cellular changes in the oviduct and endometrium that directly promote embryo development and implantation competence. The plasma fraction of seminal fluid plays a key role in this process with soluble factors, including TGFB, prostaglandin-E, and TLR4 ligands, demonstrated to contribute to the peri-conception immune environment. Recent studies show that conception in the absence of seminal plasma in mice impairs embryo development and alters fetal development to impact the phenotype of offspring, with adverse effects on adult metabolic function particularly in males. This review summarises our current understanding of the molecular responses to seminal fluid and how this contributes to the establishment of pregnancy, generation of an immune-regulatory environment and programming long-term offspring health.
    No preview · Article · Jul 2015 · Advances in Experimental Medicine and Biology
    • "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.
    No preview · Article · Dec 2014 · Cold Spring Harbor perspectives in biology
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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.
    Full-text · Article · Aug 2014 · Journal of Molecular Signaling
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