Activating T regulatory cells for tolerance in early pregnancy - the contribution of seminal fluid.
ABSTRACT 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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ABSTRACT: The ability of spermatozoa to generate reactive oxygen species (ROS) has been appreciated since the 1940's. It is a universal property of mature spermatozoa from all mammalian species and a major contributor to the oxidative stress responsible for defective sperm function. The mechanisms by which oxidative stress limits the functional competence of mammalian spermatozoa involves the peroxidation of lipids, the induction of oxidative DNA damage and the formation of protein adducts. ROS production in these cells involves electron leakage from the sperm mitochondria, triggered by a multitude of factors that impede electron flow along the electron transport chain. The net result of mitochondrial ROS generation is to damage these organelles and initiate an intrinsic apoptotic cascade as a consequence of which spermatozoa lose their motility, DNA integrity and vitality. This pathway of programmed senescence also results in the exteriorization of phosphatidylserine, which may facilitate the silent phagocytosis of these cells in the aftermath of insemination, in turn influencing the female tract immune response to sperm antigens and future fertility. Despite the vulnerability of sperm to oxidative stress, it is also clear that normal sperm function depends on low levels of ROS generation in order to promote the signal transduction pathways associated with capacitation. Modulators of ROS generation by spermatozoa may therefore have clinical utility in regulating the fertilizing capacity of these cells and preventing the development of anti-sperm immunity. Achievement of these objectives will require a systematic evaluation of pro- and anti- oxidant strategies in vivo and in vitro.Journal of Andrology 08/2012; 33(6). DOI:10.2164/jandrol.112.016535 · 1.69 Impact Factor
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ABSTRACT: Ongoing proteomic analyses are providing a wealth of new data on the composition of the sperm proteome across a range of mammals and other taxa. Although molecular evolution and functional genomic analyses of the proteome have only begun recently, we now broadly understand the molecular composition of sperm. Systems level analysis has revealed a variety of molecular insights into sperm evolution and function, including a remarkable diversity of immunity-related proteins within the proteome. Using existing mammalian sperm proteomes as a starting point, we provide an overview of this important class of sperm proteins and what is known about their function in sperm maturation, sperm quality, sperm competition, and fertilization. The recent observation that many sperm immunity proteins are rapidly evolving, presumably under the influence of positive selection, suggests that they may be responding not only to selection associated with host immunity defense but also with pleiotropic functions in sperm. In addition to the documented role of sperm in the mediation of female immune response, we propose that the fundamental mechanisms involved in cell-cell recognition and binding in both immune processes and fertilization may underlie the multi-functionality of proteins in immunity and reproductive systems.Systems biology in reproductive medicine 08/2012; 58(4):218-28. DOI:10.3109/19396368.2012.700442 · 1.70 Impact Factor
- Recent Advances in Research on the Human Placenta, 03/2012; , ISBN: 978-953-51-0194-9