Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease driven by the production of autoantibodies, which variably affect multiple organs and tissues. SLE is notoriously heterogeneous, arising from numerous possible mechanisms and there is no current efficient treatment. Previously, our lab has shown that removal of the transmembrane activator and cyclophilin ligand interactor (TACI) in a mouse model of SLE mediated by excessive B cell activating factor of the TNF family (BAFF) protects mice from disease. We investigated whether deletion of TACI in mice deficient for the Src-family protein tyrosine kinase Lyn (Lyn-/- mice) would also be beneficial. Lyn-/- mice develop autoimmunity resembling human SLE, where hyper-reactive B cells are over-activated to produce autoreactive antibodies against cellular elements. Flow cytometry was used to characterise B cell and antibody-secreting plasma cell subsets. Autoantibody detection and serum cytokine levels were measured using ELISA. The severe B cell deficit in Lyn-/- mice was not improved in Lyn-/- TACI-/- mice, however deletion of TACI in Lyn-/- mice prevented disease by significantly reducing plasma cell numbers to levels of healthy WT mice, leading to reduced autoantibody production as measured by both ELISA and immunofluorescence staining. IL6 levels were decreased to WT levels, reducing harmful inflammation and disease progression. These data provide increased support for choosing TACI as a key target for therapeutic intervention, which may be applicable in treating multiple subtypes of SLE. This would offer treatment efficacy without the serious adverse events linked with extensive loss of B cells