This program project grant application seeks support for basic experimental studies on immune recognition which will further our ability to exploit the immune system in medicine. The antigen recognition elements of the immune system, B derived immunoglobulin and the T cell receptor, are formed by the somatic rearrangement of gene elements in developing immune cells. The T cell receptor repertoire is subject to selection for self-recognition of the major histocompatibility complex encoded in class I and class II antigens during thymocyte ontogeny. Dr. Sherman will employ mice which are transgenic for a human HLA gene to assess the importance of evolutionary and somatic selection pressures in shaping the T cell response. Dr. Bevan will continue to analyze the precise lineage relationships during thymocyte ontogeny and the role of receptor interactions with self major histocompatibility molecules during T cell ontogeny. In Project IV, Dr. Sprent will study the consequences of foreign antigen recognition by CD4+ T cells during bone marrow transplantation. Protective and destructive effects may result from receptor recognition of antigen in this system. In Project II Dr. Lerner will attempt to exploit the almost unlimited potential diversity of antibody combining sites for the generation of antibodies which can cleave the peptide bond. Progress in this area may result in sequence-specific restriction proteases which would have many applications in medical research and in therapy.