The objectives of this project are to identify and characterize mechanisms by which histocompatibility-linked immune response (Ir) genes regulate antibody production. The antibody responses by inbred strains of mice to the synthetic terpolymer L-glutamic acid-L-alanine-L-tyrosine (GAT) and pork insulin are two model systems currently under investigation. Some inbred strains of mice produce antibody to these antigens, others do not. Continuing studies of the more well-characterized GAT system will focus on the mechanism by which Ir genes regulate the development of GAT-specific helper and suppressor T cells in responder and nonresponder mice. The mechanism by which GAT-specific regulatory T cells modulate immunity will be probed by functional analysis of soluble, antigen-specific, Ia-bearing, T cell replacing factors. Insulin-specific culture and assay techniques are currently under development and will be continued. Once this technology is established, the expression of Insulin-specific Ir genes in T cells, B cells and macrophages will be determined. Identification and characterization of the H-2 linked Ir gene defects in nonresponder mice will provide valuable insights into regulatory mechanisms operative in normal immune responses. This knowledge should lead to a better appreciation of the mechanisms of disease processes with immunological components and to the development of rational therapeutic measures to correct immunological imbalances.