The aim of the proposed study is to understand the rules governing interactions of developing T lymphocytes with their accessory cells and to be able to predict the outcome of such interactions. These processes are fundamental to the ability of higher vertebrates to create a functional immune system since they play a key role in imprinting and maintaining tolerance as well as creating a functional T lymphocyte repertoire. Therefore, this study will provide important insights into questions how auto-aggression develops in the so-called auto-immune diseases. The knowledge of the mechanisms involved is crucial not only to our understanding of human and animal health and illness, but will also help to design strategies to fight autoimmune diseases. T lymphocytes of all maturation stages can respond positively and negatively to engagement of their T cell antigen receptor. During T cell ontogeny positive and negative effects create the T lymphocyte repertoire. A model system is proposed in which developing thymocytes are forced to interact with thymic stroma at different times during their maturation. This will be achieved by specific monoclonal antibodies, the so-called hybrid antibodies, that ligate markers on T lymphocytes, including the T cell antigen receptor, to different structures on thymic stroma cells. Thus, it will be possible to evaluate the importance of different surface molecules on thymocytes and stroma cells for thymic education. Furthermore, the role of subpopulations of thymic stroma in imprinting thymic selection will be examined. In parallel hybrid antibodies that cross-link structures on the thymocyte surface, like CD4 or CD8, to the T cell antigen receptor will be produced to study triggering mechanisms of developing T lymphocytes.
