HIF1α is required for NK cell metabolic adaptation during virus infection

  1. Francisco Victorino  Is a corresponding author
  2. Tarin Bigley
  3. Eugene Park
  4. Cong-Hui Yao
  5. Jeanne Benoit
  6. Liping Yang
  7. Sytse J Piersma
  8. Elvin J Lauron
  9. Rebecca M Davidson
  10. Gary Patti
  11. Wayne M Yokoyama  Is a corresponding author
  1. Washington University School of Medicine, United States
  2. Washington University, United States
  3. National Jewish Health, United States
  4. University of Iowa, United States

Abstract

Natural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1α (HIF-1α) is a feature of mouse NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF-1 α -deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1α KO NK cells however, their numbers were significantly reduced. Loss of HIF-1 α did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found HIF-1α -deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF-1α -deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1α-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.

Data availability

Data generated or analyzed during this study has been deposited to the Dryad Digital Depository, available here: doi:10.5061/dryad.n5tb2rbvm

The following data sets were generated

Article and author information

Author details

  1. Francisco Victorino

    Rheumatology Division, Washington University School of Medicine, St. Louis, United States
    For correspondence
    ramirezvictorino@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7626-3219
  2. Tarin Bigley

    Rheumatology Division, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Eugene Park

    Rheumatology Division, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2617-7571
  4. Cong-Hui Yao

    Department of Chemistry, Department of Medicine, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeanne Benoit

    Department of Biomedical Research, Center for Genes, Environment and Health, National Jewish Health, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Liping Yang

    Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sytse J Piersma

    Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5379-3556
  8. Elvin J Lauron

    Rheumatology Division, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rebecca M Davidson

    Department of Biomedical Research, Center for Genes, Environment and Health, National Jewish Health, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Gary Patti

    FOEDRC Metabolomics Core Facility, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3748-6193
  11. Wayne M Yokoyama

    Department of Medicine, Washington University School of Medicine, St Louis, United States
    For correspondence
    yokoyama@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0566-7264

Funding

National Institute of Environmental Health Sciences (R35ES028365)

  • Gary Patti

National Institute of Allergy and Infectious Diseases (R01-AI131680)

  • Wayne M Yokoyama

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20180293) of the University of Washington in St. Louis School of Medicine.

Copyright

© 2021, Victorino et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,121
    views
  • 332
    downloads
  • 14
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Francisco Victorino
  2. Tarin Bigley
  3. Eugene Park
  4. Cong-Hui Yao
  5. Jeanne Benoit
  6. Liping Yang
  7. Sytse J Piersma
  8. Elvin J Lauron
  9. Rebecca M Davidson
  10. Gary Patti
  11. Wayne M Yokoyama
(2021)
HIF1α is required for NK cell metabolic adaptation during virus infection
eLife 10:e68484.
https://doi.org/10.7554/eLife.68484

Share this article

https://doi.org/10.7554/eLife.68484

Further reading

    1. Computational and Systems Biology
    2. Immunology and Inflammation
    Lucia Csepregi, Kenneth Hoehn ... Sai T Reddy
    Research Article

    Diverse antibody repertoires spanning multiple lymphoid organs (i.e., bone marrow, spleen, lymph nodes) form the foundation of protective humoral immunity. Changes in their composition across lymphoid organs are a consequence of B-cell selection and migration events leading to a highly dynamic and unique physiological landscape of antibody repertoires upon antigenic challenge (e.g., vaccination). However, to what extent B cells encoding identical or similar antibody sequences (clones) are distributed across multiple lymphoid organs and how this is shaped by the strength of a humoral response remains largely unexplored. Here, we performed an in-depth systems analysis of antibody repertoires across multiple distinct lymphoid organs of immunized mice and discovered that organ-specific antibody repertoire features (i.e., germline V-gene usage and clonal expansion profiles) equilibrated upon a strong humoral response (multiple immunizations and high serum titers). This resulted in a surprisingly high degree of repertoire consolidation, characterized by highly connected and overlapping B-cell clones across multiple lymphoid organs. Finally, we revealed distinct physiological axes indicating clonal migrations and showed that antibody repertoire consolidation directly correlated with antigen specificity. Our study uncovered how a strong humoral response resulted in a more uniform but redundant physiological landscape of antibody repertoires, indicating that increases in antibody serum titers were a result of synergistic contributions from antigen-specific B-cell clones distributed across multiple lymphoid organs. Our findings provide valuable insights for the assessment and design of vaccine strategies.

    1. Immunology and Inflammation
    Yue Yang, Bin Huang ... Fangfang Zhang
    Research Article Updated

    Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.