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

Abstract

SummaryIn 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.

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

“…Furthermore, rIL-2 supplementation during the expansion phase of the CD8 + T cell response to DC-OVA vaccination did not rescue SLEC generation, suggesting that Notch affects SLEC differentiation independently of Blimp-1. A possible mechanism by which Notch regulation of CD25 expression could affect SLEC differentiation is via modulation of T cell metabolism, as IL-2 signaling is known to regulate the activity of the Akt/mTOR pathway (52)(53)(54)(55). This possibility is in agreement with the very recent observation of Backer et al (50), who have shown reduced activation of the Akt-mTOR pathway in Notchdeficient CD8 + Te cells.…”

Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes

“…In contrast, low CD3-ITAM multiplicity is sufficient for ERK signaling, but not for proliferation. Moreover, Akt is not required for the metabolic reprogramming and proliferation of T cells (24).…”

Tsc1 promotes the differentiation of memory CD8 + T cells via orchestrating the transcriptional and metabolic programs

“…Notably, mTOR can be activated by Akt-independent pathways in effector CD8 + T cells (14,25), and deletion of Pten does not cause significant defects in memory formation (23). Here we circumvented the requirements of mTOR signaling in naïve T-cell homeostasis (27)(28)(29) and immediate TCR activation (10), by specific ablation of Tsc1 in antigen-experienced CD8 + T cells.…”

“…Moreover, whether mTOR or the canonical activator Akt impacts memory T-cell differentiation via metabolic pathways or other pathways such as cell migration is unclear (24). Of note, Akt regulates the differentiation and function of effector CD8 + T cells via orchestrating the transcriptional program instead of cellular metabolism (25). Therefore, the upstream and downstream mechanisms for mTOR-dependent regulation of memory generation remain to be defined.…”