REGULATING ANTIGEN PRESENTATION BY HUMAN FEMALE REPRODUCTIVE TRACT CELLS

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The female reproductive tract (FRT) is a unique system that must be protected from infection by pathogens, yet must also accept allogeneic spermatozoa and conceptuses. Thus, unlike their peripheral blood counterparts, immune cells within the FRT are influenced by sex hormones in a manner consistent with these dual functions. Our studies in both the human and rat have demonstrated that sex hormones have profound effects on T cell activation by FRT antigen presenting cells (APC), and provide the foundation for the current proposal, which is designed to test the hypothesis that the inductive arm of the immune system is hormonally regulated within the human FRT. Questions to be addressed are: (1) Can human FRT epithelial cells present antigens?; (2) How do epithelial cell- leukocyte interactions modulate T cell activation?; (3) By what mechanism(s) does endocrine balance modulate antigen presentation?; and (4) Does Fc receptor targeting enhance antigen presentation by FRT cells? We will isolate pure populations of epithelial cells and professional APC from each FRT tissue and characterize their efficiency of antigen presentation in response to antigen (tetanus toxoid; defined peptides; allogeneic APC) and polyclonal T cell activators (anti-CD3; bacterial super-antigen). We will then determine how epithelial and stromal cell populations modulate professional APC (macrophages and dendritic cells) phenotype, maturation, and efficiency for T cell activation, and will use blocking antibodies and soluble receptors to evaluate the cytokines and signaling molecules that influence T cell activation by APC. We will also examine how sex hormones and cytokines, which fluctuate during the menstrual cycle, alter the phenotype or function of APC either directly or via effects on stromal and epithelial cell populations. Finally, based on observations that T cell activation is markedly enhanced by targeting antigen to Fc receptors, we will determine the FRT APC for which IgG- and IgA-receptor targeting enhances antigen presentation, as well as the effects of cytokines and sex hormones on this pathway. These studies will thus result in the systematic analysis of the identity and antigen presenting efficiency of APC populations naturally present at each of the different human FRT tissue sites. Thus, we will investigate mechanisms including processing, presentation, and provision of co- stimulatory signals and cytokines necessary for T cell activation, leading to an understanding of how sex hormones and cytokines act, either directly on APC or through effects on nearby cells, to increase or decrease APC function. Overall, these studies should significantly increase our knowledge about the hormonal influences on induction and/or suppression of immune responses in this critical organ system, and lay the foundation for developing realistic approaches to the development of vaccines for sexually transmitted diseases.