The purpose of this study was to determine whether Ag presentation takes place in the female reproductive tract and if the stage of the reproductive cycle, sex hormones, and IL-6 regulate uterine Ag presentation. Purified epithelial and mixed stromal cells were incubated with sensitized lymph node T lymphocytes in the presence of OVA. Ag presentation was highest at proestrus, the stage of the reproductive cycle that immediately precedes ovulation when estradiol levels peak, and lowest at estrus, when sperm enter the uterus in preparation for fertilization. Further, these studies demonstrate that estradiol given to ovariectomized rats increases uterine cell Ag presentation relative to that in controls. In the presence of mouse anti-rat Ia Ab, Ag presentation was blocked, indicating that Ag presentation by uterine cells is MHC class II restricted. In studies to analyze Ag presentation at sites distal to the female reproductive tract, we found that Ag presentation by adherent cells from the spleen is elevated at proestrus relative to that at other stages of the estrous cycle. When IL-6 was placed in the uterine lumen of ovariectomized rats, Ag presentation by epithelial and mixed stromal cells as well as mitogenesis by spleen cells were increased significantly relative to those in controls. These studies demonstrate that the female reproductive tract is an inductive site for immune responses and that mucosal immune protection may be either enhanced or suppressed depending on the endocrine balance when the female reproductive tract is exposed to pathogens.