Our long-term objectives in this proposal are to elucidate the nature and role of T cells that regulate autoantibody production in systemic lupus erythematosus (SLE), to develop approaches to modulate these T cells, and identify potentially novel therapeutic strategies for SLE. SLE is a chronic autoimmune disease that affects multiple organs. Organ damage is mostly caused by autoantibodies, particularly antibodies to native DNA. The production of these disease-causing anti-DNA antibodies is regulated by auto-reactive T helper cells. These T helper cells react with peptides derived from the heavy chain variable (VH) regions of anti-DNA antibodies or from histones. Tolerizing or inactivating these Th cells by their specific peptide ligands delays disease development and prolongs survival in mouse mod s of SLE, such as the NZB/W female mouse. However, the induction and maintenance of tolerance requires multiple i.v. injections of large doses of these peptides; this is cumbersome and expensive. Moreover, initial attempts to treat NZB/W mice that have established nephritis with a similar i.v. peptide regimen have not been successful. Therefore, instead of tolerizing CD4+ T helper cells to control autoantibody production, we will test whether CD8+ T cells specific for VH peptides block or terminate autoantibody production I y suppressing or killing autoantibody-secreting B cells. Specifically we will test the hypothesis that minigenes that encode autoantibody VH region peptides activate regulatory or cytotoxic CD8+ T cells that specifically inhibit autoantibody production and suppress disease lupus mice. We will construct recombinant adenovirus or naked DNA vectors that encode the VH peptides, and determine their ability to activate regulatory or cytotoxic CD8+ T cells, decrease anti&#8209;DNA antibodies, and influence disease in lupus mice. To further augment CD8+ T cell activation, we will construct peptide ubiquitin fusion genes, which might enhance induction of regulatory or cytotoxic T cell responses by routing peptide into the MHC class I pathway. Development of methods that activate regulatory and cytotoxic T lymphocytes will provide new, more specific ways to control disease in patients with SLE and might have general applicability in vaccination, cancer immunotherapy and treatment of immune-mediated disorders. The studies will also elucidate the role of self-reactive CD8+ T cells in SLE.