Background <p>Chimeric antigen receptor T-cell (CAR-T) therapy, an emerging immunotherapy, has shown promising efficacy in several autoimmune diseases. In this study, we conducted a preclinical evaluation of the therapeutic potential of CD19-specific CAR-T cell–mediated B-cell depletion in a mouse model that recapitulates key features of human IgG4-related disease (IgG4-RD).</p> Methods <p>B cell depletion strategies were evaluated in the <i>Lat</i>^Y136F mouse model, a spontaneous murine model of IgG4-RD. Anti-CD19 CAR-T cells or control cells were transferred into <i>Lat</i>^Y136F mice pretreated with total body irradiation. <i>Lat</i>^Y136F mice treated with anti-CD20 monoclonal antibodies (mAb) served as the positive control group.</p> Results <p>CD19-targeted CAR-T cell infusion resulted in a more profound depletion of B cells and plasmablasts compared to anti-CD20 mAb treatment. This depletion was observed in peripheral blood, spleen, lacrimal glands, lungs, and pancreas in <i>Lat</i>^Y136F mice. Moreover, CAR-T cell therapy significantly prolonged the survival of <i>Lat</i>^Y136F mice and improved clinical symptoms compared to anti-CD20 mAb treatment. However, while CAR-T cell therapy reduced inflammation and fibrosis in the lacrimal glands and pancreas, it did not improve these conditions in the lungs.</p> Conclusions <p>Our findings demonstrate that anti-CD19 CAR-T therapy effectively alleviates the progression of IgG4-RD, showing superior efficacy compared to anti-CD20 mAb in this preclinical model. These results support further investigation of CAR-T cells as a potential therapeutic option for IgG4-RD patients, with attention to potential adverse effects.</p>