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Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors

Nature Reviews Immunology volume 5, pages 712–721 (2005)Cite this article

Key Points

  • It should be appreciated that the oxygen tensions in inflamed tissues, and even in normal tissues, are usually low (that is, these tissues are hypoxic).

  • The molecular mechanisms that ensure adaptation to hypoxia are operational in immune cells, thereby enabling immune surveillance in all tissue microenvironments and preventing 'safe shelters' for pathogens.

  • Activated immune cells mainly rely on glycolysis, rather than on oxidative phosphorylation, as a source of energy.

  • Hypoxia can regulate the activity of immune cells by promoting accumulation of adenosine and by stabilizing hypoxia-inducible factor 1α (HIF1α).

  • Inhibition of HIF1 might have different effects in various types of immune cell. HIF1α deficiency in myeloid cells results in reduced inflammation. By contrast, in T cells, HIF1α is thought to be a negative regulator of activity.

  • HIF1 is a promising therapeutic target for modulating immune responses. Inhibition or upregulation of HIF1α might induce or reduce inflammation depending on the type of immune response.

Abstract

Immune cells are often exposed to low oxygen tensions, which markedly affect cellular metabolism. We describe how activated T cells adapt to the changing energy supplies in hypoxic areas of inflamed tissues by using hypoxia-inducible factor 1 (HIF1) to switch to glycolysis as the main source of energy and by signalling through extracellular-adenosine receptors. This hypoxic regulation might alter the balance between T helper 1 cells and T helper 2 cells and might alter the activities of cells of the innate immune system, thereby qualitatively and quantitatively affecting immune responses. This regulatory mechanism should be taken into account in the design and interpretation of in vitro and in vivo studies of immune-cell effector functions.

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Figure 1: Low oxygen concentration in tissue environments.
Figure 2: Simplified schema of glycolysis and oxidative phosphorylation.
Figure 3: The hypothesis: role of hypoxia in local tissues in the regulation of T cells in inflamed and hypoxic areas.
Figure 4: Simplified schema of the regulation of HIF1α levels by oxygen tension.
Figure 5: Simplified schema showing the effects of HIF1α in different immune cells.

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Acknowledgements

This work was supported, in part, by a grant from the National Institutes of Health (United States) to M.S.

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  1. New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, 134MU, Boston, 02115, Massachusetts, USA

    Michail Sitkovsky & Dmitriy Lukashev

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  1. Michail Sitkovsky
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Correspondence to Michail Sitkovsky.

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DATABASES

Entrez Gene

A2AR

A2BR

FIH1

HIF1α

PHD1

PHD2

PHD3

SIAH1A

SIAH2

VHL

Glossary

ACTIVATION-INDUCED CELL DEATH

A mechanism of elimination of potentially autoreactive T cells. It occurs through Tcell-receptor-mediated activation, which produces a block in the cell cycle followed by apoptotic death.

RECOMBINATION-ACTIVATING GENE 2 (RAG2)-DEFICIENT BLASTOCYST-COMPLEMENTATION SYSTEM

A gene-targeting technique used for the genetic analysis of lymphocytes. Complementation of RAG2-deficient blastocysts (which cannot produce mature T or B cells) with embryonic stem cells that have a mutation in the gene of interest creates chimeras that have genetically altered T and B cells.

B1 CELL

A cell belonging to the B-cell lineage that mainly populates the peritoneum and secretes polyspecific, low-affinity IgM.

B2 CELL

A conventional B cell. These cells reside in secondary lymphoid organs and secrete antigen-specific antibodies.

Cre–loxP TECHNOLOGY

A method for targeting specific genes by homologous recombination using the bacteriophage P1 recombinase Cre, which recognizes specific loxP sites in target DNA and catalyses recombination between these sites. This results in the excision of the DNA sequence between them.

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Sitkovsky, M., Lukashev, D. Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors. Nat Rev Immunol 5, 712–721 (2005). https://doi.org/10.1038/nri1685

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