Abstract
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 was designed to investigate the mechanisms by which inhibition of glycolysis with 2-deoxy-d-glucose (2DG) reduces the expansion of T (FH) cells and the associated autoantibody production 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, which include an increased chaperone-mediated autophagy induced by TLR7 activation. Importantly, adoptive transfer of 2DG-reprogrammed T (FH) cells protected lupus-prone mice from disease progression. 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 of targeting glycolysis to eliminate aberrant T (FH) cells and curb the production of autoantibodies inducing tissue damage.