Hypoxia-inducible factors in T lymphocyte differentiation and function. A Review in the Theme: Cellular Responses to Hypoxia

Abstract

Low oxygen concentrations or hypoxia is a trait common to inflamed tissues. Therefore it is not surprising that pathways of hypoxic stress response, largely governed by hypoxia-inducible factors (HIF), are highly relevant to the proper function of immune cells. HIF expression and stabilization in immune cells can be triggered not only by hypoxia, but also by a variety of stimuli and pathological stresses associated with leukocyte activation and inflammation. In addition to its role as a sensor of oxygen scarcity, HIF is also a major regulator of immune cell metabolic function. Rapid progress is being made in elucidating the roles played by HIF in diverse aspects of both innate and adaptive immunity. Here we discuss a number of breakthroughs that have shed light on how HIF expression and activity impact the differentiation and function of diverse T cell populations. The insights gained from these findings may serve as the foundation for future therapies aimed at fine-tuning the immune response.

Keywords: T cells; hypoxia-inducible factor; immune activation; inflammation; metabolism.

Fig. 1.

Regulation of hypoxia-inducible factor-1 (HIF-1) expression and function by multiple inputs. Across diverse cell types, HIF-1 is regulated at the protein level by oxygen-dependent mechanisms (panel 1). HIF subunits are readily transcribed. However, in the presence of oxygen, proline residues of the HIF-1α subunit are hydroxylated by prolyl hydroxylase domain (PHD) enzymes (which are inactive under hypoxic conditions). Modified HIF-1 molecules then interact with the von Hippel-Lindau (VHL)/E3 ligase complex, become polyubiquitinated, and are then degraded by the 26S proteasome. Additionally, hydroxylation of residue N803 can disrupt interaction with transcription cofactors. In immune cells, and particularly T cells, HIF-1 expression can be transcriptionally upregulated even in the presence of oxygen in response to stimuli triggering Toll-like receptor (TLR), T cell receptor (TCR), costimulation signaling pathways leading to mammalian target of rapamycin (mTOR) pathway activation (panel 2).

Fig. 2.

A combinational approach for enhancing the anti-tumor immune response through HIF-1-targeting approaches. Inhibition of HIF-1 activity or expression (1) undermines expression of Th17-associated genes including the tumor-abetting IL-17. Disrupting HIF-1 also enhances the frequency of a highly proinflammatory subset of CD8⁺ T cells capable of driving more effective anti-tumor immune responses. While HIF-1 inhibition is expected to elevate frequencies of potentially suppressive Foxp3⁺ T cells as well, simultaneous depletion or inhibition of Tregs (2) is likely to either prevent this counterproductive potentiality or enhance anti-tumor immunity further.