Lymphocyte activation and tolerance continues to be an important topic of much theoretical and practical significance. The projects in this program are linked by a common interest in this subject. Overall, their goal is to find out how circumstances control the response, or lack of response, or a lymphocyte to antigen. This control is important both to our ability to generate efficient vaccines and to understand autoimmune disease. Experiments to be done in project 1 will deal with a new model of B cell tolerance in which self antigens make B cells non-responsive in such a way that their responsiveness can easily be regenerated. In project 2, the investigators will study the geography of the interface between thymocytes and tolerising or selecting ligand. The investigators will also study the interface between CD8+ T cells and antigen presenting cells. The investigators of project 3 have found that the pro-apoptotic protein BAD is crucial to the decision of activated T cells to live or die. The structure and function of BAD in different types of T cells will therefore be investigated together with the structure of BAD bound to its anti- apoptotic ligand, Bcl-xl. These three projects are coordinated not only in their common interest in lymphocyte activation but also by their common use of two technologies, which will be supported by the two Cores, in flow cytometry and digital microscopy.