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.