InterFeriNg with Acetγlation: Stress-Levels of Acetate Improve Memory T Cell Function  Caroline A. Lewis, Matthew G. Vander Heiden  Immunity  Volume 44, Issue 6, Pages 1243-1245 (June 2016) DOI: 10.1016/j.immuni.2016.06.004 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Systemic Levels of Acetate Increase in Response to Infection, Leading to Increased IFN-γ Production and impacting T Cell Metabolism Increased acetate levels in response to bacterial infection result in increased acetate in T cells that is activated to acetyl-CoA in the mitochondria by acetyl-CoA synthetase 1 (ACSS1), converted into citrate, and then exported back into the cytosol where it is recovered as acetyl-CoA by ATP citrate lyase (ACLY). This results in an expanded cytosolic acetyl-CoA pool that in turn increases acetylation of the glycolytic enzyme glycerol-3-phosphate dehydrogenase (GAPDH), increasing its activity. Both increased GAPDH activity and glucose are required for IFN-γ production, resulting in improved recall function of CD8+ memory T cells exposed to acetate. Increased GAPDH activity might also contribute to enhanced glycolysis that accompanies T cell activation. Although ACSS1 and ACLY were implicated in the production of IFN-γ, it is also possible that a second pool of acetate is activated in the cytosol by ACSS2, which could then be used to support fatty acid synthesis (FAS), as well as fatty acid oxidation (FAO), a mechanism that has also been shown to occur in memory T cells (O’Sullivan et al., 2014). CS, citrate synthase; PDH, pyruvate dehydrogenase; FAS, fatty acid synthesis; FAO, fatty acid oxidation; ACSS1, acetyl-CoA synthetase 1; ACSS2, acetyl-CoA synthetase 2; GAPDH, glycerol-3-phosphate dehydrogenase; IFN-γ, interferon-γ; ACLY, ATP-citrate lyase; OAA, oxaoloacetate. Immunity 2016 44, 1243-1245DOI: (10.1016/j.immuni.2016.06.004) Copyright © 2016 Elsevier Inc. Terms and Conditions