The role of glycolysis in lymphocyte survival and autoimmunity

Abstract

It is well established that constitutively enhanced glycolytic activity in tumor cells confers a selective advantage and inhibitors of glycolysis, such as 2‐deoxyglucose (2‐DOG), can inhibit tumor growth. The growth and survival of normal B and T lymphocytes following activation also is dependent on upregulation of glycolytic activity and is inhibited by 2‐DOG. Here, we ask whether diseases characterized by chronic lymphocyte stimulation such as systemic autoimmunity are associated with dysregulated glycolysis. Studies were performed with mice deficient in FasL (gld/gld) that develop lymphoproliferative disease and autoimmunity. We found that B cells from gld mice had significantly elevated levels of mRNA transcripts for glycolytic enzymes and increased hexokinase II, a key regulatory enzyme in glycolysis. To determine the effects of glycolysis inhibition on activated lymphocytes in vivo, we treated mice for 10 days with 2‐DOG. This resulted in a significant reduction in both T and B cells with selective depletion of activated CD4+ and CD8+ (CD44hi) and B cells (CD23loCD21lo), suggesting these cells are particularly dependent on enhanced glycolysis for survival. Studies are in progress to determine whether prolonged therapy with glycolysis inhibitors reduces autoantibody titers in autoimmune models. This work was supported by an Arthritis Foundation Chapter Research Grant awarded to W.F.D.