INHERITED CONTROL MECHANISMS IN IG GENE EXPRESSION

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The broad objective of this research is to provide new information on the mechanism of Lyl+ T cell tolerance for self Ig. We recently developed an immunoglobulin-dependent T cell proliferation assay that measures Lyl+ T cell reactivity to self and nonself Ig. Using allotype congenic mice, we demonstrated that responding Lyl+ T cells recognize allotypic determinants present on the foreign Ig and that this response is sensitive to tolerance induction. The fact that the antigen is well characterized structurally, easily quantitated by standard techniques, naturally present in serum and under normal physiological conditions also exists as an integral membrane glycoprotein, as well as the availability of a well defined genetic polymorphism and allotype congenic mouse strains, provide this system with unique advantages for studying the cellular basis of tolerance. The major goal of the proposed investigation is to identify the types of cells that participate in tolerance induction. Adult thymectomized mice, radiation-induced bone marrow chimeras, experimentally agammaglobulinemic, and allotype-suppressed mice will be used as tools to characterize the target population and further define the role played by B cells. The possibility that Ly2+ suppressor T cells may be involved in the induction and/or maintenance of Lyl+ T cell tolerance will be tested. Specific structural features of the IgG2a molecule required for tolerance induction will be described. Moreover, a wide panel of myeloma and hybridoma proteins, including mutant monoclonal antibodies with well characterized structural alterations are available for analyzing the possible relationship between immunogenic and tolerogenic determinants. In sum, these studies will hopefully lead to a clearer understanding of cellular events in tolerance and processes involved in immunoglobulin homeostasis.