Mitochondrial Ca2+ and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function
Rui Yang,
Dario Lirussi,
Tina M Thornton,
Dawn M Jelley-Gibbs,
Sean A Diehl,
Laure K Case,
Muniswamy Madesh,
Douglas J Taatjes,
Cory Teuscher,
Laura Haynes,
Mercedes Rincón
Affiliations
Rui Yang
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
Dario Lirussi
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
Tina M Thornton
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
Dawn M Jelley-Gibbs
Trudeau Institute, Saranac Lake, United States
Sean A Diehl
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
Laure K Case
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
Muniswamy Madesh
Department of Medical Genetics and Molecular Biochemistry, Temple University, Philadelphia, United States; Center for Translational Medicine, Temple University, Philadelphia, United States
Douglas J Taatjes
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, United States; Microscopy Imaging Center, University of Vermont, Burlington, United States
Cory Teuscher
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
Laura Haynes
Trudeau Institute, Saranac Lake, United States
Mercedes Rincón
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
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.
