PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells

Abstract

A PI3K- and Akt-independent pathway mediated by mTORC1 regulates expression of HIF1 in CD8+ T cells and is required to sustain glucose metabolism and regulate cell trafficking.

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

“…Moreover, the enhanced glycolytic function is in accordance with the observed increase in the highly entangled hypoxia and HIF1α-related pathways. 40 These differences may be related to differences in experimental T cell activation models and inhibitor dosing. Furthermore, as downstream targets of AKT, including mTORC1, can also be regulated via other pathways, this may have contributed to different effects on hypoxia, HIF1α targets, and glucose metabolism.…”

“…Furthermore, as downstream targets of AKT, including mTORC1, can also be regulated via other pathways, this may have contributed to different effects on hypoxia, HIF1α targets, and glucose metabolism. 40 Moreover, our assays were performed using naïve CD8 + T cells only, whereas others mainly used total PBMCs. Nevertheless, though also in natural memory subsets, including T SCM cells, oxidative metabolism is described to be more dominant, 27 a recent publication on autoreactive T SCM cells also observed an increased glycolytic profile.…”

mTOR signaling and transcriptional regulation in T lymphocytes

“…The transcription factor hypoxia-inducible factor 1 (HIF1) is induced early during T cell activation in an mTOR-dependent manner. 8,22,46 Although its deficiency does not affect initial T cell activation, proliferation or metabolic reprogramming, 8,22 HIF1 is required for sustained glycolysis and pyruvate metabolism in effector CD8 + T cells. Furthermore, HIF1-deficient effector CD8 + T cells have defective expression of perforin and certain granzymes, but not other effector molecules, such as interferon-γ, suggesting that the mTORC1-HIF1 axis regulates a specific transcriptional program in effector CD8 + T cells.…”

“…Furthermore, HIF1-deficient effector CD8 + T cells have defective expression of perforin and certain granzymes, but not other effector molecules, such as interferon-γ, suggesting that the mTORC1-HIF1 axis regulates a specific transcriptional program in effector CD8 + T cells. 8 TCR-induced mTOR signaling promotes HIF1 protein synthesis, likely through 4E-BP1-eIF4 mediated capdependent translation. 31,46 Interferon regulatory factor 4 (IRF4) is a transcription factor critical for many immune cell differentiation and function.…”

“…8 Recent studies have demonstrated that mTOR signaling is extensively involved in lymphocyte biology. Numerous immune signals, including T cell receptor (TCR), co-stimulatory signals and various cytokines, activate mTOR, which in turn regulates lymphocyte metabolism and dictates lineage differentiation and immune functions.…”