Figure 1.

Metabolic pathways in T cells. T-cell activation by T-cell receptor (TCR)/CD28 co-stimulation and growth factors/cytokines such as IL-2 or IL-7 activate AKT through phosphoinositide 3-kinase (PI3K) induction in a similar manner to insulin, inducing increase of glucose uptake and glycolysis. The switch to glycolysis allows production of the requisite ATP and biosynthetic substrates that are required for proliferation, cytokine synthesis and other T-cell functions. AKT activates mammalian target of rapamycin (mTOR), which increases the expression of amino acid transporters and glycolysis. Inflammation can also lead to hypoxia and reduced nutrient supply. Low ATP levels activate AMP activated protein kinase (AMPK), which upregulates catabolic processes, such as fatty acid oxidation, and downregulates anabolic metabolism. AMPK can inhibit mTOR via raptor and lead to cell-cycle arrest. Hypoxia induces hypoxia inducible factor (HIF) expression via mTOR activity. HIF-1 forms tertiary complexes with RORĪ³t and p300, and enhances inflammation-promoting Th17 cell development through recruitment to the IL-17 promoter or upregulation of glycolysis. Concurrently, HIF-1 attenuates inflammation-restricting regulatory T cell (Treg) development by binding Foxp3. HIF-1 induces migration inhibitory factor (MIF), which in turn causes HIF-1 expression via the MIF receptor (MIF-R) in a positive feedback loop. The AMPK stimulator metformin and the mTOR inhibitor rapaymcin are able to augment fatty acid oxidation and can increase Treg generation.

Spies et al. Arthritis Research & Therapy 2012 14:216   doi:10.1186/ar3885
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