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

  • Immunology in Colorado
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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.

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Abbreviations

EPO:

Erythyropoietin

FoxP3:

Forkhead box P3

HIF:

Hypoxia inducible factor

HRE:

Hypoxia response element

IBD:

Inflammatory bowel disease

IEL:

Intraepithelial lymphocyte

kPa:

Kilopascal

mm Hg:

Millimeter of mercury

PHD:

Prolyl hydroxylase

TCR:

T cell receptor

Tregs:

Regulatory T cells

VEGF:

Vascular endothelial growth factor

VHL:

von Hippel-Lindau

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Acknowledgments

The authors were funded in part by National Institutes of Health grants R01 AI093637-01A1 and U19 AI050864 P&F to DH and a Crohn’s and Colitis Foundation of America grant to ENM. The authors thank Dr. Holger Eltzschig for critical discussion and ongoing support, and Dr. Linda van Dyk for critical review.

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Mucosal Inflammation Program, Department of Anesthesiology, School of Medicine, University of Colorado Denver, Aurora, CO, 80045, USA

    Eóin N. McNamee, Darlynn Korns Johnson, Dirk Homann & Eric T. Clambey

  2. Integrated Department of Immunology, National Jewish Health, University of Colorado Denver, Aurora, CO, 80045, USA

    Darlynn Korns Johnson & Dirk Homann

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  1. Eóin N. McNamee
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  2. Darlynn Korns Johnson
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Correspondence to Eric T. Clambey.

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McNamee, E.N., Korns Johnson, D., Homann, D. et al. Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol Res 55, 58–70 (2013). https://doi.org/10.1007/s12026-012-8349-8

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