TCR Engagement Increases Hypoxia-Inducible Factor-1α Protein Synthesis via Rapamycin-Sensitive Pathway under Hypoxic Conditions in Human Peripheral T Cells

Abstract

Peripheral T cells encounter rapid decrease in oxygen tension because they are activated by Ag recognition and migrate into inflammatory sites or tumors. Activated T cells, therefore, are thought to have such machineries that enable them to adapt to hypoxic conditions and execute immune regulation in situ. We have recently shown that survival of CD3-engaged human peripheral blood T cells is prolonged under hypoxic conditions and hypoxia-inducible factor-1 (HIF-1) and its target gene product adrenomedullin play a critical role for the process. It is also shown that hypoxia alone is not sufficient, but TCR-mediated signal is required for accumulation of HIF-1α in human peripheral T cells. In the present study, we showed that TCR engagement does not influence hypoxia-dependent stabilization but stimulates protein synthesis of HIF-1α, most possibly via PI3K/mammalian target of rapamycin system, and that expression of HIF-1α and its target genes is blocked by treatment with rapamycin. Since some of those gene products, e.g., glucose transporters and phosphoglycerokinase, are considered to be essential for glycolysis and energy production under hypoxic conditions and adequate immune reaction in T cells, this TCR-mediated synthesis of HIF-1α may play a pivotal role in peripheral immune response. Taken together, our results may highlight a novel aspect of downstream signal from Ag recognition by TCR and a unique pharmacological role of rapamycin as well.

Requirements for T Lymphocyte Migration in Explanted Lymph Nodes

“…Hypoxia inducible factor controls the expression levels of several essential genes that are required for cell and tissue adaptation to hypoxia including glucose transporters, glycolytic enzymes, vascular endothelial cell growth factor, NO synthase, and erythropoietin (55,56). T cell activation also up-regulates glucose transporters and glycolytic enzymes (57), perhaps to prepare the cells for entry into hypoxic environments.…”

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…The transcription factor hypoxia-inducible factor 1α (HIF1α) is positively regulated by PI3K-AKT-mTOR signals 101,102 . HIF1α induces the expression of genes that are required for glycolysis when stabilized by low oxygen availability.…”

Cutting Edge: Hypoxia-Inducible Factor 1α and Its Activation-Inducible Short Isoform I.1 Negatively Regulate Functions of CD4+ and CD8+ T Lymphocytes

“…HIF-1␣ expression in T lymphocytes can be induced both by hypoxia (16) and by non-hypoxic pathways, including TCRtriggered and PI3K-mediated pathways, resulting in mRNA up-regulation and protein stabilization (17)(18)(19). We previously demonstrated that T cell activation leads to "immediate early response gene" up-regulation of the alternative mRNA isoform of HIF-1␣ I.1 (20), which contains a different first exon and is expressed from self promoter in a immune tissue-specific manner (21,22).…”