B Lymphocytes Impede Tregs to Erode Islet Tolerance in Type 1 Diabetes

B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur without B cells challenges this view. Still, preclinical and clinical studies have shown that B-cell depletion alleviates β-cell destruction, suggesting a critical role for B cells in T1D. Our findings propose an alternative function for B cells, impairing regulatory T cells (Tregs) that would otherwise protect islets. In the NOD islet transplant model, we show that B-cell absence enables transplant tolerance, allowing Tregs to become responsive to immune therapy and confer allograft protection. Extending this to spontaneous diabetes, we have found that insulin-reactive Tregs are reduced in NOD mice in proportion to insulin-reactive B cells, while effector T cells remain unaffected. Moreover, Tregs from B-cell–deficient NOD mice better restrained β-cell destruction than those from B-cell–sufficient environments. Together, these findings indicate that autoreactive B cells primarily erode immune regulation by culling islet-protective Tregs. Thus, therapies that mobilize Tregs could be more effective when combined with B-cell–targeting strategies in islet transplant or T1D prevention. Article Highlights This study expands the role of B lymphocytes in type 1 diabetes by demonstrating how B cells influence the development and function of regulatory T cells (Tregs) during islet transplant and autoimmune progression. This study was done to explain how B lymphocytes regulate the progression of anti-islet immunity, even when they appear dispensable for effector cell activation. B-cell deficiency (using NOD.μMT mice) enables durable islet transplant tolerance, enhances the expansion of Helios+ Tregs, increases the ratio of insulin-reactive Tregs to effector T cells, and enhances islet-protective Treg function. These findings indicate that B lymphocytes accelerate destructive immunity by negatively regulating Treg development and function. Targeting the harmful B-cell–Treg interactions, particularly in the thymic environment, may offer new, more selective therapeutic strategies to prevent anti-islet immunity.