Glycolysis inhibition functionally reprograms T follicular helper cells and reverses lupus

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the production of pathogenic autoantibodies depends on T follicular helper (T FH ) cells. This study investigated the mechanisms by which the glycolysis inhibitor 2-deoxy- d -glucose (2DG) reduces the expansion of T FH cells and the associated production of autoantibodies in lupus-prone mice. Integrated cellular, transcriptomic, epigenetic, and metabolic analyses showed that 2DG reversed the enhanced cell expansion and effector functions, as well as mitochondrial and lysosomal defects in lupus T FH cells, including increased expression of chaperone-mediated autophagy (CMA) markers associated with Toll-like receptor 7 activation. Importantly, adoptive transfer of 2DG-reprogrammed T FH cells protected lupus-prone mice from disease progression. The orthologs of genes responsive to 2DG in murine lupus T FH cells were overexpressed in the T FH cells of SLE patients, suggesting a therapeutic potential for targeting glycolysis to eliminate aberrant T FH cells and curb the production of autoantibodies that induce tissue damage.