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Studies in mice demonstrate that the maternal T cell repertoire is aware of paternal antigens during pregnancy, but in healthy pregnancy reactive T cells do not mediate anti-fetal immunity. Mice expressing transgenic T cell receptors (TCRs) specific for paternal and conceptus antigens are powerful tools for elucidating the events surrounding paternal antigen presentation to the maternal T cell repertoire, the nature of the ensuing T cell response and the factors that skew the response towards immune tolerance to allow survival and development of the conceptus. While results from different transgenic TCR models are not always consistent, there is now sufficient data to allow a consensus interpretation that maternal antigen presenting cells present initially seminal fluid antigens and later placenta-derived antigens to both the CD4+ and CD8+ T cell repertoire. T cell proliferation is generally followed by entry into a state of anergy demonstrated by decreased cytokine production and hyporesponsiveness upon restimulation. Some models also demonstrate downregulation of the TCR and co-stimulatory molecules, clonal deletion of paternal antigen-reactive T cells, or alternatively T cell ignorance of paternal antigens. This review will summarise the range of transgenic TCR studies that have shed light on the events surrounding paternal antigen presentation and the various T cell responses to insemination and pregnancy. The benefits, limitations and caveats of these models, and their impact upon data interpretation, are discussed. Refereed/Peer-reviewed

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 TGFβ 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 Refereed/Peer-reviewed