Article

Protein Kinase B Controls Transcriptional Programs that Direct Cytotoxic T Cell Fate but Is Dispensable for T Cell Metabolism

College of Life Sciences, Division of Cell Biology & Immunology, University of Dundee, Scotland, UK.
Immunity (Impact Factor: 19.75). 02/2011; 34(2):224-36. DOI: 10.1016/j.immuni.2011.01.012
Source: PubMed

ABSTRACT In cytotoxic T cells (CTL), Akt, also known as protein kinase B, is activated by the T cell antigen receptor (TCR) and the cytokine interleukin 2 (IL-2). Akt can control cell metabolism in many cell types but whether this role is important for CTL function has not been determined. Here we have shown that Akt does not mediate IL-2- or TCR-induced cell metabolic responses; rather, this role is assumed by other Akt-related kinases. There is, however, a nonredundant role for sustained and strong activation of Akt in CTL to coordinate the TCR- and IL-2-induced transcriptional programs that control expression of key cytolytic effector molecules, adhesion molecules, and cytokine and chemokine receptors that distinguish effector versus memory and naive T cells. Akt is thus dispensable for metabolism, but the strength and duration of Akt activity dictates the CTL transcriptional program and determines CTL fate.

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    • "+/+ ) (Figures 5A, 5B, and S3A). Cytokine production by FoxO1 fl/fl CTLs was only modestly affected, but the expression of granzyme B, a FoxO1-repressed target gene (Macintyre et al., 2011; Hess Michelini et al., 2013; Rao et al., 2012; Tejera et al., 2013), was markedly increased (Figures 5C, 5D, and S3B). Despite this, viral loads remained significantly higher in FoxO1 fl/fl relative to FoxO1 +/+ mice, probably owing to a combination of decreased proliferation and survival of LCMVspecific CTLs in the absence of FoxO1 as suggested by Ki67 and by the ratio of Bim to Bcl-2 staining, respectively (Figures 5E–5G and S3C; Kim et al., 2013; Tejera et al., 2013). "
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    • "Effector T cells strikingly increase their cellular uptake of multiple nutrients including glucose, amino acids and transferrin. They also swap from metabolising glucose primarily through oxidative phosphorylation to become highly glycolytic [1]–[4]. The changes in effector T cell metabolism are important as judged by the consequences of inhibiting key metabolic regulators. "
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    • "Many of these Teff cell subsets maintain an elevated glycolytic rate in response to cytokine signaling and display different cell metabolic phenotypes. In response to IL-2 signaling, CTL maintain high levels of glucose uptake and lactate production indicative of elevated glycolysis [70]. It is reported that anergic T cells are also metabolically anergic as evidenced by the failure of the up-regulation of the essential machinery to support increased metabolism upon full stimulation [51]. "
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