Systemic Lupus Erythematosus (SLE) is a potentially fatal autoimmune disease characterized by the production of pathogenic autoantibodies that recognize nucleic acid containing antigens. These antibodies form immune complexes that promote tissue damage in multiple organs and perpetuate a systemic inflammatory environment. The majority of current therapies for SLE involve non-specific immunosuppression and have undesirable side effects. Thus there is an urgent need for more targeted therapies. Recent studies have demonstrated that autoreactive B cells have unique requirements for their activation, participation in germinal centers, and differentiation into antibody secreting plasma cells compared to B cells reactive with foreign antigens. Understanding the consequences of these differential signals may reveal new therapeutic strategies to prevent autoimmune responses while maintaining the ability to respond to infection. The transcription factor T-bet is a) upregulated by stimuli that are uniquely required for autoreactive B cell responses and b) increased in germinal center B cells and ABCs in mouse lupus models and in DN2 cells from SLE patients. ABCs and DN2s are B cell subsets that accumulate in lupus and differentiate efficiently into plasma cells that secrete elevated levels of autoantibodies. However, the degree to which T-bet expressing B cells contribute to the production of pathogenic autoantibodies is unclear, as prior results have been contradictory. A better understanding of this is necessary in order to support these cells as a therapeutic target for lupus. We posit that T-bet expression is a marker for cells that give rise to autoantibodies in lupus models, even if it is not itself absolutely required for autoantibody production. We will test this hypothesis by 1) using a fate mapping strategy to determine the contribution of cells that express, or once expressed, T-bet to the accumulation of autoreactive plasma cells, and 2) preventing T-bet expressing B cells from differentiating into plasma cells in a lupus model. Successful completion of these studies will highlight T-bet expressing B cells or stimuli that induce them as potential therapeutic targets for SLE. The methods developed here to delete genes specifically in T-bet expressing B cells will also be valuable for future mechanistic studies involving these cells both in autoimmune disease and during immune response to infections.