Glutamine-Dependent Biosynthetic Pathways Fuel Autoreactive T and B Cells in Foxp3 Deficiency-mediated Disease

Foxp3 deficiency causes a profound loss of immune tolerance, unleashing autoreactive T and B cells, lymphoproliferation, cytokine-driven inflammation, and autoantibody production. This autoimmune pathology is fueled by increased glutamine usage, but it remains unresolved whether glutamine is necessary to produce energy, or for biosynthetic pathways leading to inosine and asparagine production. Here, we demonstrate that glutamine utilization supports Foxp3-deficiency mediated disease independently of pathogenic Foxp3-deficient Treg cell energetic reprogramming. Mechanistically, glutamine biosynthetic pathways sustain conventional T cell activation and proinflammatory cytokine production preventing inosine accumulation and signaling, thus implicating adenosine pathway modulation in autoreactive T cell dysregulation. Conversely, autoreactive B cell activation and autoantibody production depend on glutamine-dependent asparagine synthesis, which we reveal as a targetable vulnerability for autoantibody formation. These findings highlight glutamine-driven biosynthetic processes as critical drivers of autoimmunity and reveal distinct metabolic vulnerabilities in autoreactive T and B cells that can be targeted for therapeutic intervention.