The Migration of Peripheral Macrophages to TNCs and Their Role in Antigen Presentation

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Project Abstract: The migration of peripheral macrophages to thymic nurse cells and their role in antigen presentation.T cells ultimately function to remove virally infected cells from the body. In order for them to accomplish this task, T cells have to be able to distinguish cells that are a part of the body, called self-cells, from agents that are foreign to the body. During development in the thymus, self antigens are presented to developing T cells. The T cells through their antigen receptor (TcR) have the ability to recognize antigens on the surfaces of the antigen presenting (APC) thymic cells. When a self-antigen is presented to developing T cells, its TcR binds tightly to this protein on the surface of an APC and that T cell is induced to die through a process called apoptosis. This makes sense because if the T cell was allowed to mature and released in the blood stem, it would recognize that antigen and kill the normal B cell to which it was attached. Mature T cells are able to determine which self-cells are infected with viruses and which produce foreign proteins on the cell surface. This is most important when one realizes that viruses live and hide inside of the cells that they infect. The Guyden lab has developed cell lines from one of the APCs that function during this process and are called thymic nurse cells (TNCs). These cells are unique to the body because they actually take up developing thymocytes into their cytoplasm during antigen presentation. A major question yet to be answered is, how does all of the large number of self antigens get to the thymus for antigen presentation, when most self antigens reside outside of the thymus? Preliminary results show that other antigen presenting cells like macrophages and dendritic cells exist within this TNC complex along with developing thymocytes. Further, the macrophages that are stained and returned to the gut of a mouse can migrate to the thymus and into TNCs. It is proposed that macrophages and dendritic cells, which have a primary function of removing dead and apoptotic cells from the body, have the ability to present self antigens resulting from dead cells to developing T cells within the TNC complex. Studies using genetically manipulated animals that have T cells with only one TcR will be carried out. Migration of macrophages or dendritic cells transferred into the gut of these animals will be followed and their ability to induce apoptosis in developing T cells in large enough numbers will be determined statistically. An antibody to TNCs has also been developed and will be used to treat normal mice, which will result in the elimination of their TNCs. The population of T cells that mature from these treated animals will be analyzed. If TNCs function during antigen presentation and self-antigen cannot be presented in their absence, mature T cell that have the ability to attack self cells or are auto-immunogenic will be detected. Broader Impact: Minority students will be trained and will be involved in this project. Funds coming from this project will allow the training of seven PhD students. Over the years of NSF funding, 38 minority undergraduate students have participated in research in the laboratory and have since obtained their PhD or MD degrees or are continuing students. Currently, there are: 1 PhD, 2 Masters, and 3 undergraduate students.