Understanding the innate and inductive arms of the immune system in the FRT is of critical importance because of its implications for the reproductive health of women. Strategies to induce local immune protection have developed slowly because of the paucity of information on reproductive tract immunobiology, the role of sex hormones, and significant differences between the upper and lower FRT responses to inflammation. In particular, little is known about mechanisms within reproductive tract tissues that guide the differentiation of monocytes into pro- versus anti-inflammatory macrophages and DCs. This information is fundamentally important since macrophages and DCs are critical both as rapid effectors of innate immunity and as the antigen presenting cells (APCs) responsible for initiation of adaptive immune responses. By defining the influences of sex hormones on myeloid cells in general and within the FRT, protocols may be devised to effectively treat venereal diseases and human infertility. The central focus of this application is to characterize the effects of estrogen, progesterone, and testosterone on myeloid cells and to test the hypothesis that endocrine and cytokine balance plays a critical role in both innate and adaptive immune responses. This hypothesis derives from our studies on antigen presentation by cells from the human and rat FRT, which show a strong correlation with estradiol levels. To accomplish these goals, we propose to test the following hypotheses. The first hypothesis is that sex hormones, acting either directly or indirectly, influence the differentiation of monocytes into macrophages and DCs. We would examine the effects of sex hormones, alone and in combination, during the differentiation and maturation of monocytes into macrophages and DCs and their role in the maintenance of tolerance. The second hypothesis is that sex hormones and menstrual status influence myeloid cell functions, which are differentially regulated according to their location in the FRT. We would examine how sex hormones affect macrophage-mediated phagocytosis, extracellular killing, and modulation of T cell responses. We would compare pro- and anti-inflammatory responses and determine how sex hormones influence these fundamental macrophage effector mechanisms. The third hypothesis is that sex hormones and stage of menstrual status modulate lymphocyte proliferation and/or cytolytic activity via indoleamine 2,3-dioxygenas (IDO). We hypothesize that IDO is the key regulatory element blocking T cell activity in the FRT. Specifically, we would address regulation of IDO by sex hormones and whether it is responsible for reduced cell proliferation and non-lytic activity of CD8+ T cells seen during the secretory phase of the cycle. The fourth hypothesis is that endocrine balance regulates the capacity of macrophages and DCs to initiate an adaptive immune response. We would target antigen to receptors associated with innate (mannose receptor) and adaptive (CD64 and CD89) immunity and determine the effects of sex hormones on processing and presentation of antigen by macrophages and DCs.
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