Targeting MCT1 suppresses humoral response and autoimmunity via the NAD(H) redox state

Immunometabolism has garnered significant attention due to its essential roles in regulating B cell activation, proliferation and differentiation. Monocarboxylate transporters (MCTs), a family of solute carrier transporters responsible for lactate transport across biological membranes, have been shown to play a pivotal role in immune responses across various immune cell types. However, the expression and functional significance of MCTs in B cells remain poorly understood. In this study, we demonstrated that germinal center B cells and activated B cells exhibit elevated levels of MCT1 expression. Pharmacologically blocking MCT1 with AZD3965 inhibited both T-cell dependent and independent humoral response and ameliorated autoimmunity in the experimental autoimmune myasthenia gravis. Mechanically, MCT1 blockade led to the accumulation of intracellular lactate, which in turn suppressed NAD + regeneration, thereby inhibiting B cell activation and survival. Taken together, these findings suggest that MCT1 might be a potential therapeutical target in antibody-mediate autoimmune disease.