Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function

Abstract

Oxygen is a molecule that is central to cellular respiration and viability, yet there are multiple physiologic and pathological contexts in which cells experience conditions of insufficient oxygen availability, a state known as hypoxia. Given the metabolic challenges of a low oxygen environment, hypoxia elicits a range of adaptive responses at the cellular, tissue, and systemic level to promote continued survival and function. Within this context, T lymphocytes are a highly migratory cell type of the adaptive immune system that frequently encounters a wide range of oxygen tensions in both health and disease. It is now clear that oxygen availability regulates T cell differentiation and function, a response orchestrated in large part by the hypoxia-inducible factor transcription factors. Here, we discuss the physiologic scope of hypoxia and hypoxic signaling, the contribution of these pathways in regulating T cell biology, and current gaps in our understanding. Finally, we discuss how emerging therapies that modulate the hypoxic response may offer new modalities to alter T cell function and the outcome of acute and chronic pathologies.

Fig. 1

Physiologic oxygen tensions in situ are significantly lower than atmospheric oxygen tension, with multiple tissues experiencing “physiologic hypoxia” during normal inspiration of atmospheric air. Graph depicts the range of oxygen tensions in multiple tissues (indicated at left), with published ranges of oxygen tensions indicated by the black bar on the plot. The gray shaded area, between 0 and 2 kPa, indicates the PO₂ range at which Hif-1α protein has increased stability, a marker of the hypoxic response. The vertical dashed line indicates a PO₂ of 1.3 kPa, the PO₂ at which cells generally retain nitroimidazole compounds, indicating cells or tissues experiencing hypoxia. Additional examples of tissues that stain positive with nitroimidazole compounds are indicated at the bottom of the figure. Please see text for additional details and references

Fig. 2

Hif-1α protein expression within T cells can be induced by multiple mechanisms, with distinct outcomes on magnitude and duration of Hif-1α expression. Of the three extrinsic cues known to induce Hif-1α protein (listed in the top row of the figure), each uses a distinct mechanism of induction. Examples of identified Hif-1α target genes for each pathway are included