Article | Published:

Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen

Nature Immunology volume 14, pages 11731182 (2013) | Download Citation

Abstract

Cytolytic activity by CD8+ cytotoxic T lymphocytes (CTLs) is a powerful strategy for the elimination of intracellular pathogens and tumor cells. The destructive capacity of CTLs is progressively dampened during chronic infection, yet the environmental cues and molecular pathways that influence immunological 'exhaustion' remain unclear. Here we found that CTL immunity was regulated by the central transcriptional response to hypoxia, which is controlled in part by hypoxia-inducible factors (HIFs) and the von Hippel–Lindau tumor suppressor VHL. Loss of VHL, the main negative regulator of HIFs, led to lethal CTL-mediated immunopathology during chronic infection, and VHL-deficient CTLs displayed enhanced control of persistent viral infection and neoplastic growth. We found that HIFs and oxygen influenced the expression of pivotal transcription, effector and costimulatory-inhibitory molecules of CTLs, which was relevant to strategies that promote the clearance of viruses and tumors.

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Acknowledgements

We thank members of the Zuniga Laboratory at the University of California, San Diego, for technical advice, discussions and reagents; V. Jhaveri for technical assistance; A. Best for assistance with bioinformatics; the Immunological Genome Project for microarray reagents, processing and assistance; members of the Hedrick Laboratory (University of California, San Diego) for human IL-2 ; and E. Zuniga, S. Hedrick, G. Barton and J. Harker for discussions and review of the manuscript. Supported by the US National Institutes of Health (A.W.G. and R.S.J.), the Pew Scholars Program and the Leukemia Lymphoma Society (A.W.G.), the US National Institutes of Health and University of California, San Diego, Cancer Biology Fund (A.L.D.), the University of California, San Diego, and US National Institutes of Health Cell (A.T.P.) and the Austrian Science Fund (M.H.S.).

Author information

Affiliations

  1. Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, La Jolla, California, USA.

    • Andrew L Doedens
    • , Anthony T Phan
    • , Martin H Stradner
    • , Jessica K Fujimoto
    • , Jessica V Nguyen
    • , Edward Yang
    •  & Ananda W Goldrath
  2. Division of Rheumatology and Immunology, Medical University of Graz, Graz, Austria.

    • Martin H Stradner
  3. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.

    • Randall S Johnson

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Contributions

A.L.D. designed and did experiments, analyzed the data and wrote the paper; A.T.P. designed and did experiments, analyzed data and assisted in writing the paper; M.H.S. did histological analysis, provided advice for the design and analysis of pathophysiological experiments and assisted in writing the paper; J.K.F. and J.V.N. did and analyzed viral titer experiments and assisted with animal work; E.Y. did and analyzed immunofluorescence experiments; R.S.J. provided reagents, provided advice for experimental design and wrote the paper; and A.W.G. supervised the project, designed the experiments, analyzed the data and wrote the paper.

Competing interests

A.L.D., A.T.P., R.S.J. and A.W.G. hold a provisional patent for manipulation of the VHL-HIF pathway for therapy.

Corresponding author

Correspondence to Ananda W Goldrath.

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https://doi.org/10.1038/ni.2714

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