Bcl-3 oncoprotein in T cell survival. Immunization with antigen plus adjuvant results in the rapid proliferation and clonal expansion of antigen-specific T cells. Failure to include adjuvants during immunization ultimately results in clonal deletion, rather than clonal expansion, because the responding T cells proliferate briefly but go on to die. Understanding the mechanisms by which adjuvants promote T cell survival could generate novel approaches to improve vaccines and prevent autoimmune diseases. We previously studied adjuvant-induced T cell survival in mice given natural adjuvants, which are materials from microbes that trigger innate immune responses. In activated T cells, the oncoprotein Bcl-3 was induced by adjuvants more than any other gene tested. Bcl-3 is a member of the NFkappaB/Rel/IKappaB superfamily of transcription factors, but its physiological function is unknown. It is proposed that Bcl-3 regulates activated T cell survival through an NFKB-dependent mechanism.
Specific aims : 1. Determine the extent of the Bcl-3 adjuvant effect on T cells. The hypothesis that Bcl-3 regulates T cell survival, rather than differentiation or proliferation, will be tested via retroviral gene transfer. These experiments will test the extent to which Bcl-3 expression alone is sufficient to explain the effects of adjuvants on T cells, and establish parameters within which to study its survival effect. 2. Define the structural domains and collaborating proteins needed for Bcl-3 to promote T cell survival. The hypothesis that Bcl-3 functions through an NFkappaB-dependent mechanism will be tested by assessing T cell survival after retroviral transduction of Bcl-3, of deletion mutants of Bcl-3 and of other NFkappaB family members. These experiments will identify NFKappaB proteins needed for Bcl-3 to promote lymphocyte survival, and will define domains of Bcl-3 that are necessary for it to contribute to T cell survival. 3. Identify the cell populations that cause impaired immunity in Bcl-3-deficient mice. Bc13-/- mice fail to produce specific antibodies after vaccination and fail to clear model infections, patterns which are consistent with the idea that some or all of the immune defects in these mice are caused by abortive T cell responses. Experiments with these mice will identify those adjuvant effects on T cells for which Bcl-3 expression is required and which could therefore be targeted by drug inhibition.
