Abstract Systemic lupus erythematosus (lupus) is characterized by polyclonal B cell activation, leading to the production of pathogenic class-switched autoantibodies that promote tissue injury. These B cells undergo somatic mutation and immunoglobulin isotype switching in extrafollicular (EF) sites and germinal centers (GCs) located within secondary lymphoid organs, sites of CD4+ T cell-dependent B cell maturation. Mounting evidence suggests that in lupus, autoantibody-producing B cells such as memory B cells, CD11c+Tbet+ B cells, and plasma cells are generated via both EF and GC reactions. Yet, the contribution of each of these B cell subsets to the generation and activity of autoantibodies in lupus remain unclear. CD11c+Tbet+ B cells (Tbet+ B cells herein) are a distinct B cell subset that differentiate following viral infections as well as autoimmunity in mice and humans. Emerging studies have shown that in murine and human lupus, Tbet+ B cells are critical drivers of pathogenic autoantibodies. In lupus, Tbet+ B cells are capable of differentiating into class-switched autoantibody-secreting cells upon stimulation by cytokines and TLR agonists. The presence of Tbet+ B cells in severe disease has been well elucidated, but their development and contribution as disease progresses in lupus is poorly understood. We found that the kinetics of Tbet+ B cell development and expansion in lupus-prone mice mirror the increase of autoantibodies and worsening disease state. Moreover, we show a temporal loss of the GC-derived Tbet+ B cell population coinciding with their expansion in the blood as disease progresses. We previously demonstrated that Tbet+ B cells arise predominantly independent of GCs during viral infections, and our preliminary data show that Tbet+ B cells appear to be mainly, but not exclusively, from EFs in lupus-prone mice as well. Tbet+ B cell development in requires IFN- a subset of CD4+ T helper cells, T follicular helper (Tfh) cells. These cytokines are secreted by Tfh cells throughout disease promoting pathogenic Tbet+ B cell responses. We found that CD9 expression on Tfh cells identifies the IL-21 and IFN-γ secreting subset, which we found to expanded in mice and human lupus. Our overarching hypothesis is Tbet+ B cells that arise from EF or γ and IL-21 signaling from GCs are transcriptionally and functionally distinct, but in lupus the chronic inflammatory milieu in different tissues leads to their aberrant regulation and differentiation into ASCs that contribute to disease. Accordingly, we will explore temporal changes in genetic regulation that functionally impact pathogenic Tbet+ B cell development from EF or GCs and from tissues such as the kidney in autoimmune disease. We will use unique transgenic lupus mice, combined with cellular techniques and novel genomic approaches to investigate the genetic regulation influencing function of these B cells at different stages of disease. We will also examine the requirement for the CD9-exp...