Environmental and metabolic sensors that control T cell biology

Abstract

The T lymphocyte response to pathogens is shaped by the microenvironment. Environmental sensors in T cells include the nutrient-sensing serine/threonine kinases, adenosine monophosphate-activated protein kinase and mammalian target of rapamycin complex 1. Other environmental sensors are transcription factors such as hypoxia-inducible factor-1 and the aryl hydrocarbon receptor. The present review explores the molecular basis for the impact of environmental signals on the differentiation of conventional T cell receptor αβ T cells and how the T cell response to immune stimuli can coordinate the T cell response to environmental cues.

Keywords: T cell metabolism; amino acid uptake; aryl hydrocarbon; glucose uptake; hypoxia; leucine and mTOR; microbiome.

Figure 1

A summary of the key metabolic and environmental sensors that influence T lymphocyte biology. mTORc1 is inhibited by AMPK, which is a key glucose sensor. mTORc1 is also influenced by intracellular amino acid levels such as leucine and glutamine. Oxygen tensions are sensed by HIF-1α, which remains under the control of mTORc1. Bacterial virulence factors and metabolites from dietary tryptophan are sensed by the AhR. AhR and HIF-1α have the same dimerizing partner – HIF-1β.

Figure 2

A model of the regulation and function of HIF complexes in cytotoxic T cells. Under normoxic conditions, HIF-1α is rapidly degraded. This rapid degradation occurs because proline residues of HIF-1α become hydroxylated by prolyl hydroxylases after which HIF-1α is ubiquitinated by the von-Hippel–Lindau E3 ligase complex. In hypoxia, the hydroxylation of HIF-1α does not occur and the transcription factor is no longer targeted for degradation and HIF-1α protein can thus accumulate within the cell. In effector CD4 and CD8 T cells, high levels of mTORC1 activity promote HIF-1α translation allowing moderate levels of HIF complexes to accumulate even under normoxic conditions. The different regulatory signals that control mTORc1 activity in T cells are also shown as are some of the gene targets whose expression is either promoted (blue arrows) or repressed (red lines) by HIF-1 complexes.