Dendritic cells (DCs) within peripheral tissues play a critical role in initiating immune responses towards peripheral antigens. Upon activation, these cells migrate through the tissue stroma towards lymphatic vessels, transmigrate across lymphatic endothelial cells, and travel through the duct to the draining lymph nodes (LNs) where they present antigen to T cells. At present, little is known about the signals that regulate directional DC migration within peripheral tissues other than the involvement of the chemokine receptor CCR7, which is expressed by activated DCs, and its ligand CCL21, which is expressed by lymphatic vessels. It is unclear, however, whether a lymphatic endothelial cell-derived CCL21 gradient drives the entire process of DC emigration. This proposal suggests a non-CCL21 chemo attractant factor is responsible for the initial portion of DC migration from the uterus, prior to a final CCL21-driven step of lymphatic entry. Besides being a remarkably understudied organ with regards to DC biology, due to the anatomy, the uterus provides an excellent opportunity to examine these questions concerning DC chemotaxis. The non-pregnant mouse uterus contains DCs distributed in both the endometrium and surrounding myometrium, yet only the myometrium contains lymphatic vessels. Thus, endometrial DCs must travel up to 250 ?m in order to reach the myometrial lymphatics.
In Aim I, I determine the signals that control the directional migration of DCs as they emigrate from the non-pregnant uterus.
In Aim II, I will determine whether migratory DCs at the maternal/fetal interface contribute to maternal T cell recognition of the fetal allograft. These studies will provide basic information regarding DC behavior in the uterus, an important yet understudied mucosal tissue, and will potentially lead to new insights into the general mechanisms that guide DC migration within peripheral tissues. Furthermore, my work on DC behavior during pregnancy may help elucidate how peripheral DCs decide to generate productive versus tolerogenic immune responses. Together, such insights will have implications for vaccine development, tumor immunology, the pathogenesis of autoimmune disease, and the treatment of infectious diseases of the uterus.
