Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (Treg) 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 Treg 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 Treg cells, a CRISPR-Cas9-enabled Pfkp deletion recapitulated the metabolism of Camk4-/- Treg 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 Treg cell function. In conclusion, we provide molecular insights in the defective metabolism and function of Treg cells in SLE and identify PFKP as a target to fine-tune Treg cell metabolism and thereby restore their function.