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

Abstract
Article and author information
Metrics

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

Rui Yang

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
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.
Tina M Thornton

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
Dawn M Jelley-Gibbs

Taconic, Germantown, United States

Competing interests
The authors declare that no competing interests exist.
Sean A Diehl

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
Laure K Case

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
Muniswamy Madesh

Department of Medical Genetics and Molecular Biochemistry, Temple University, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
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.
Cory Teuscher

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
Laura Haynes

Trudeau Institute, Saranac lake, United States

Competing interests
The authors declare that no competing interests exist.
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).

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.