Previous studies supported by this grant have provided a clear picture of the expression of Ia glycoprotein antigens on the lymphocyte surface. In addition, we have shown that Ia antigens are the molecular products of immune response (Ir) genes, and that quantitative as well as qualitative (allelic) differences in Ia expression influence immune response potential. The goals of the current proposal are to 1) determine the extent, nature, and functional relevance of quantitative and qualitative microheterogeneity in the expression of Ia molecules on the cell surface, which has only been peripherally explored, and 2) determine whether suppression universally accounts for nonresponsiveness in Ir nonresponder mice, and explore possible mechanisms of this nonresponsiveness (e.g. self tolerance). To achieve these goals, we will utilize conventional Ia antisera and monoclonal Ia antibodies, two dimensional gel electrophoresis, and T cells and cloned autoreactive T cell lines to probe the genetics, expression, and biology of Ir products. In addition, we will apply two novel systems which we have developed to the analysis of the role of immune suppression in self tolerance and Ir gene function (contrasuppression and stimulation in I-J disparate strains). The long term objective of this research is to determine the contribution of quantitative and qualitative microheterogeneity in Ia expression to immune response capacity, and to determine the precise mechanism(s) of Ir gene control.