Role of Toll-Like Receptors in Trophoblast Immune Regulation

Yale University, New Haven CT

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Abstract

A fundamental feature of the immune system is to protect the host from foreign bodies and to promote tissue repair. These functions depend on the innate immune system's capacity to coordinate cell migration for surveillance and to recognize and respond to invading pathogens. The human decidua contains a large number of immune cells, such as macrophages, natural killer (NK) cells and regulatory T cells (Tregs). These, as well as decidual stromal cells, produce factors, necessary for the regulation of immune responses and placental development. The appropriate communication between all these cellular components at the maternal-fetal interface is critical for successful reproduction. Our general hypothesis is that during pregnancy, the trophoblast regulates leukocyte migration, differentiation and activation. In turn, the maternal immune system responds by producing factors that promote trophoblast survival and function. We propose that trophoblast cells recognize the uterine microenvironment and respond to it by recruiting immune cells necessary for a successful pregnancy. Moreover, we postulate that Toll-Like Receptors (TLR) mediate trophoblast recognition of this environment. Thus, our central hypothesis is that TLRs expressed by the trophoblast function as sensors of the maternal-fetal interface microenvironment which induce the production of cytokines/chemokines that will, in turn, regulate immune cell distribution and function. However, if the function of TLRs is left unchecked, the implantation site may become overwhelmed by immune activation. Therefore, TLR function and signaling must be tightly regulated in order to prevent pathologic conditions. Our objectives are to: 1) understand the function of TLRs in first trimester trophoblast cells;2) determine the effects of trophoblast TLR activation on maternal immune cells;3) characterize the regulatory mechanisms controlling TLR expression and function at the maternal-fetal interface;and 4) evaluate the role of TLRs in pregnancy outcome. Therefore, our specific aims are to: Aim 1. Determine the cytokine profile in first trimester trophoblast cells following TLR activation. Aim 2. Characterize the effect of trophoblast TLR activation on immune cell recruitment and function. Aim 3. Study the regulation of TLR expression and function in trophoblast cells. Aim 4. In vivo studies for the characterization TLR function in pregnancy.