Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity
Marc Scherlinger, Wenliang Pan, Ryo Hisada, Afroditi Boulougoura, Nobuya Yoshida, Milena Vukelic, Masataka Umeda, Suzanne Krishfield, Maria Tsokos, George C. Tsokos
Abstract
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.