We have demonstrated IL-2 + anti-CD3 Ab stimulated CTL activity exists throughout the human female reproductive tract (RT). T cells from secretory phase uterine endometrium, however, lack lytic function despite the presence of substantial numbers of CD3+CD8+ T cells. High circulating levels of estradiol (E2) and progesterone (P) are present during the secretory phase, when embryo implantation many occur. Low levels of E2/P, present post-menopausally, correlated with the highest levels of endometrial CTL activity. Thus, CTL activity was found to correlate inversely with E2/P hormones within the endometrium, possibly to avoid rejection of the semi-allogeneic embryo. High CTL activities were consistently found in the cervix and vagina, suggesting maximal immunologic protection is provided at these sites. Our overall hypothesis is that CD3+CD8+ T cell lytic function within the female RT is regulated by sex steroid hormones and that this regulation of T cells allows for reproduction while maximizing immune protection. The primary goals of this proposal are to define the mechanisms by which RT CTL lytic function is regulated and to define the involvement of other immune cells, such as T helper cells, macrophages, and NK cells in these pathways. To address these goals we will: 1) define the cell-to-cell interactions that are responsible for the low/no versus high CTL activity phenotypes. An assessment of T cell activation state, proliferative ability, and susceptibility to apoptosis will be included as well. 2) identify how cytokines modulate RT T cell function. Both the production of cytokines and regulation of function by cytokines in vitro will be assessed. 3) evaluate the effect of sex steroid hormones and other steroids on RT T cell function. The effects of endogenous E2/P on T cell cytolytic activity will continue to be analyzed, Modulation of cytokine production, proliferation and differentiation of RT lymphocytes by exogenous E2/P will also be evaluated. The implications of this research are relevant for fertility/infertility, protection against STD, menopausal health concerns, cancer, and other female RT disorders.
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