1. Immunology and Inflammation
Download icon

Mitochondrial Ca2+ and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function

  1. Rui Yang
  2. Dario Lirussi
  3. Tina M Thornton
  4. Dawn M Jelley-Gibbs
  5. Sean A Diehl
  6. Laure K Case
  7. Muniswamy Madesh
  8. Douglas J Taatjes
  9. Cory Teuscher
  10. Laura Haynes
  11. Mercedes Rincón  Is a corresponding author
  1. University of Vermont, United States
  2. Helmholtz Center for Infection Research, Germany
  3. Taconic, United States
  4. Temple University, United States
  5. Trudeau Institute, United States
Research Article
  • Cited 39
  • Views 4,853
  • Annotations
Cite this article as: eLife 2015;4:e06376 doi: 10.7554/eLife.06376

Abstract

IL-6 plays an important role in determining the fate of effector CD4 cells and the cytokines that these cells produce. Here we identify a novel molecular mechanism by which IL-6 regulates CD4 cell effector function. We show that IL-6-dependent signal facilitates the formation of mitochondrial respiratory chain supercomplexes to sustain high mitochondrial membrane potential late during activation of CD4 cells. Mitochondrial hyperpolarization caused by IL-6 is uncoupled from the production of ATP by oxidative phosphorylation. However, it is a mechanism to raise the levels of mitochondrial Ca2+ late during activation of CD4 cells. Increased levels of mitochondrial Ca2+ in the presence of IL-6 are used to prolong Il4 and Il21 expression in effector CD4 cells. Thus, the effect of IL-6 on mitochondrial membrane potential and mitochondrial Ca2+ is an alternative pathway by which IL-6 regulates effector function of CD4 cells and it could contribute to the pathogenesis of inflammatory diseases.

Article and author information

Author details

  1. Rui Yang

    Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Dario Lirussi

    Department of Vaccinology and Applied Microbiology, Helmholtz Center for Infection Research, Braunschweig, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Tina M Thornton

    Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dawn M Jelley-Gibbs

    Taconic, Germantown, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sean A Diehl

    Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Laure K Case

    Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Muniswamy Madesh

    Department of Medical Genetics and Molecular Biochemistry, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Douglas J Taatjes

    Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Cory Teuscher

    Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Laura Haynes

    Trudeau Institute, Saranac lake, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Mercedes Rincón

    Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
    For correspondence
    mrincon@uvm.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All procedures performed on the mice were approved by the Institutional Animal Care and Use Committee (IACUC) of University of Vermont using protocols #12-032 (Rincon), #11-024 (Teuscher) and by the IACUC of Trudeau Institute using protocol #03-005 (Haynes).

Reviewing Editor

  1. Ruslan Medzhitov, Howard Hughes Medical Institute, Yale University School of Medicine, United States

Publication history

  1. Received: January 7, 2015
  2. Accepted: May 13, 2015
  3. Accepted Manuscript published: May 14, 2015 (version 1)
  4. Version of Record published: May 29, 2015 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 4,853
    Page views
  • 876
    Downloads
  • 39
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

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)

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

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

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Philipp Kolb et al.
    Research Article Updated

    Human cytomegalovirus (HCMV) is endowed with multiple highly sophisticated immune evasion strategies. This includes the evasion from antibody mediated immune control by counteracting host Fc-gamma receptor (FcγR) mediated immune control mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). We have previously shown that HCMV avoids FcγR activation by concomitant expression of the viral Fc-gamma-binding glycoproteins (vFcγRs) gp34 and gp68. We now show that gp34 and gp68 bind IgG simultaneously at topologically different Fcγ sites and achieve efficient antagonization of host FcγR activation by distinct but synergizing mechanisms. While gp34 enhances immune complex internalization, gp68 acts as inhibitor of host FcγR binding to immune complexes. In doing so, gp68 induces Fcγ accessibility to gp34 and simultaneously limits host FcγR recognition. The synergy of gp34 and gp68 is compelled by the interfering influence of excessive non-immune IgG ligands and highlights conformational changes within the IgG globular chains critical for antibody effector function.

    1. Cell Biology
    2. Immunology and Inflammation
    Shannon M Walsh et al.
    Tools and Resources

    The detection of foreign antigens in vivo has relied on fluorescent conjugation or indirect read-outs such as antigen presentation. In our studies, we found that these widely used techniques had several technical limitations that have precluded a complete picture of antigen trafficking or retention across lymph node cell types. To address these limitations, we developed a 'molecular tracking device' to follow the distribution, acquisition, and retention of antigen in the lymph node. Utilizing an antigen conjugated to a nuclease-resistant DNA tag, acting as a combined antigen-adjuvant conjugate, and single-cell mRNA sequencing we quantified antigen abundance in lymph node. Variable antigen levels enabled the identification of caveolar endocytosis as a mechanism of antigen acquisition or retention in lymphatic endothelial cells. Thus, these molecular tracking devices enable new approaches to study dynamic tissue dissemination of antigen-adjuvant conjugates and identify new mechanisms of antigen acquisition and retention at cellular resolution in vivo.