Selective CAR T cell-mediated B cell depletion suppresses the IFN signature in systemic lupus erythematosus (SLE). This study used single-cell RNA sequencing and T/B cell repertoire analysis to investigate the molecular changes in immune signatures following CD19 CAR T cell-mediated B cell depletion in SLE patients. The results showed a selective reset of the B cell response and a significant reduction in type I IFN signaling in monocytes and T cells. These findings suggest a causal relationship between B cell activity and the increased IFN signature in SLE. The study also demonstrates the utility of combining targeted therapies with molecular analysis to understand immune-mediated inflammatory diseases. SLE is an autoimmune disease characterized by chronic inflammation and autoantibody production. B cells play a key role in SLE pathogenesis, contributing to autoantibody production and immunological memory. An increased type I IFN signature is a hallmark of SLE, and blocking IFN signaling has shown therapeutic benefit in some patients. However, the exact mechanisms linking B cells and IFN signaling in SLE remain unclear. CD19 CAR T cells have shown promise in B cell depletion, particularly in SLE and other B cell-mediated autoimmune diseases. This study analyzed the effects of CD19 CAR T cell therapy on the immune status of SLE patients, revealing a profound reduction in type I IFN signaling and a reset of the B cell compartment. The results suggest that CD19 CAR T cell therapy effectively reduces autoimmunity by targeting B cells and decreasing IFN signaling. The study also showed that CD19 CAR T cell therapy does not significantly alter the composition of other immune cell subsets, such as monocytes and T cells. The B cell receptor repertoire was altered, with a reduction in memory B cells and an expansion of transitional B cells. The findings support the role of B cells in driving the IFN signature in SLE and highlight the potential of CD19 CAR T cell therapy as a targeted treatment for SLE. The study provides insights into the molecular mechanisms underlying SLE and supports the use of precision medicine approaches in autoimmune diseases.Selective CAR T cell-mediated B cell depletion suppresses the IFN signature in systemic lupus erythematosus (SLE). This study used single-cell RNA sequencing and T/B cell repertoire analysis to investigate the molecular changes in immune signatures following CD19 CAR T cell-mediated B cell depletion in SLE patients. The results showed a selective reset of the B cell response and a significant reduction in type I IFN signaling in monocytes and T cells. These findings suggest a causal relationship between B cell activity and the increased IFN signature in SLE. The study also demonstrates the utility of combining targeted therapies with molecular analysis to understand immune-mediated inflammatory diseases. SLE is an autoimmune disease characterized by chronic inflammation and autoantibody production. B cells play a key role in SLE pathogenesis, contributing to autoantibody production and immunological memory. An increased type I IFN signature is a hallmark of SLE, and blocking IFN signaling has shown therapeutic benefit in some patients. However, the exact mechanisms linking B cells and IFN signaling in SLE remain unclear. CD19 CAR T cells have shown promise in B cell depletion, particularly in SLE and other B cell-mediated autoimmune diseases. This study analyzed the effects of CD19 CAR T cell therapy on the immune status of SLE patients, revealing a profound reduction in type I IFN signaling and a reset of the B cell compartment. The results suggest that CD19 CAR T cell therapy effectively reduces autoimmunity by targeting B cells and decreasing IFN signaling. The study also showed that CD19 CAR T cell therapy does not significantly alter the composition of other immune cell subsets, such as monocytes and T cells. The B cell receptor repertoire was altered, with a reduction in memory B cells and an expansion of transitional B cells. The findings support the role of B cells in driving the IFN signature in SLE and highlight the potential of CD19 CAR T cell therapy as a targeted treatment for SLE. The study provides insights into the molecular mechanisms underlying SLE and supports the use of precision medicine approaches in autoimmune diseases.