Phosphofructokinase P Fine-Tunes T Regulatory Cell Metabolism, Function and Stability in Systemic Autoimmunity

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (T reg ) cells. Here, we demonstrate that a T cell–specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6. lpr lupus-prone mice and expands T reg cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In T reg cells, a CRISPR-Cas9–enabled Pfkp deletion recapitulated the metabolism of Camk4 −/− T reg cells and improved their function and stability in vitro and in vivo. In SLE CD4 + T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced T reg cell function. In conclusion, we provide molecular insights in the defective metabolism and function of T reg cells in SLE and identify PFKP as a target to fine-tune T reg cell metabolism and thereby restore their function.