Pyruvate Kinase Muscle (PKM)-2 promotes CD4 T cell survival by regulating pyruvate oxidation during homeostasis and expansion

Glycolysis is an essential metabolic pathway for rapidly expanding T cells, but role of Pyruvate Kinase Muscle (PKM) 1 and 2 in regulating this process is underappreciated. Here, using a pharmacological activator and targeted deletion of PKM2 in T cells we delineated distinct functions of PKM1 and 2 in regulating CD4 T cell survival during homeostasis and expansion. Expanding PKM2-deficient CD4 T cells increased PKM1 expression with associated mitochondrial ROS-mediated cell death. Examination of T cell compartments revealed PKM2-deficient CD4 T cells were unaltered in the thymus but were significantly reduced in peripheral tissues as mice aged. The failure of PKM1 to protect CD4 T cells in the absence of PKM2 resulted in protection from T cell mediated colitis as pathogenic cell numbers were significantly reduced resulting in less severe disease compared to control cells. This study shows PKM2 is critical for CD4 T cell survival during expansion and homeostasis. Overall design: Naïve T cells were isolated from spleen and lymph nodes of wild type or Pkm2 knockout mice. Cells were cultured for 24 hours with IL7 alone (resting) or IL7 plus plate-bound aCD3 and aCD28 antibodies.