A role for Noxa in human primary T cell activation and metabolic reprogramming (LYM4P.756)

Upon activation, T cells undergo changes to meet the metabolic demands of proliferation, including the upregulation of aerobic glycolysis. The expression of the Bcl-2 protein Mcl-1 and paradoxically that of its pro-apoptotic binding partner Noxa is also upregulated. Studies showing Noxa is post-translationally modified in both primary and leukemic human T cells, such that its death function is masked, suggest that Noxa plays a direct role in T cell proliferation and survival. Our data show that Noxa also regulates metabolic flux in Jurkat T cells. Here we evaluate Noxa’s role in early proliferation and metabolic reprogramming of human primary T cells. Surprisingly glutamine, but not glucose, was essential for Noxa induction following stimulation. T cells stimulated in the absence of glucose or glutamine exhibit an activated phenotype comparable to controls although cell viability was low in the absence of glucose. The high oxygen consumption and low extracellular acidification rates (OCR and ECAR) of glucose-deprived cells pointed to an early switch to glutamine for mitochondrial respiration during activation. Conversely, glutamine-deprived cells decreased OCR but increased glycolysis to maintain an elevated ECAR, reminiscent of the Warburg effect. We also traced the path of [13C] glucose and glutamine during this metabolic switch. Our data demonstrate for the first time how human primary T cells reprogram metabolism upon activation and how Noxa contributes to these pathways.