Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated Fatty Acid Oxidation

Brenda Raud; Dominic G Roy; Ajit S Divakaruni; Tatyana N Tarasenko; Raimo Franke; Eric H Ma; Bozena Samborska; Wei Yuan Hsieh; Alison H Wong; Philipp Stüve; Catharina Arnold-Schrauf; Melanie Guderian; Matthias Lochner; Shakuntala Rampertaap; Kimberly Romito; Joseph Monsale; Mark Brönstrup; Steven J Bensinger; Anne N Murphy; Peter J McGuire; Russell G Jones; Tim Sparwasser; Luciana Berod

doi:10.1016/j.cmet.2018.06.002

Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated Fatty Acid Oxidation

Cell Metab. 2018 Sep 4;28(3):504-515.e7. doi: 10.1016/j.cmet.2018.06.002. Epub 2018 Jun 28.

Authors

Brenda Raud¹, Dominic G Roy², Ajit S Divakaruni³, Tatyana N Tarasenko⁴, Raimo Franke⁵, Eric H Ma², Bozena Samborska², Wei Yuan Hsieh⁶, Alison H Wong², Philipp Stüve¹, Catharina Arnold-Schrauf¹, Melanie Guderian¹, Matthias Lochner¹, Shakuntala Rampertaap⁷, Kimberly Romito⁷, Joseph Monsale⁷, Mark Brönstrup⁵, Steven J Bensinger⁸, Anne N Murphy⁹, Peter J McGuire⁴, Russell G Jones¹⁰, Tim Sparwasser¹¹, Luciana Berod¹²

Affiliations

¹ Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Niedersachsen 30625, Germany.
² Goodman Cancer Research Centre, Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
³ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Metabolism, Infection, and Immunity Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
⁶ Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
¹⁰ Goodman Cancer Research Centre, Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada. Electronic address: russell.jones@mcgill.ca.
¹¹ Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Niedersachsen 30625, Germany. Electronic address: sparwasser.tim@mh-hannover.de.
¹² Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Niedersachsen 30625, Germany. Electronic address: luciana.berod@twincore.de.

Abstract

T cell subsets including effector (T_eff), regulatory (T_reg), and memory (T_mem) cells are characterized by distinct metabolic profiles that influence their differentiation and function. Previous research suggests that engagement of long-chain fatty acid oxidation (LC-FAO) supports Foxp3⁺ T_reg cell and T_mem cell survival. However, evidence for this is mostly based on inhibition of Cpt1a, the rate-limiting enzyme for LC-FAO, with the drug etomoxir. Using genetic models to target Cpt1a specifically in T cells, we dissected the role of LC-FAO in primary, memory, and regulatory T cell responses. Here we show that the ACC2/Cpt1a axis is largely dispensable for T_eff, T_mem, or T_reg cell formation, and that the effects of etomoxir on T cell differentiation and function are independent of Cpt1a expression. Together our data argue that metabolic pathways other than LC-FAO fuel T_mem or T_reg differentiation and suggest alternative mechanisms for the effects of etomoxir that involve mitochondrial respiration.

Keywords: AMPK; CD8 T cells; CPT; acetyl-CoA carboxylase; carnitine palmitoyltransferase; etomoxir; fatty acid oxidation; memory T cells; regulatory T cells.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetyl-CoA Carboxylase / genetics
Acetyl-CoA Carboxylase / physiology*
Animals
CD8-Positive T-Lymphocytes / metabolism*
Carnitine O-Palmitoyltransferase / genetics
Carnitine O-Palmitoyltransferase / physiology*
Cell Differentiation / drug effects
Cells, Cultured
Child
Child, Preschool
Epoxy Compounds / pharmacology*
Fatty Acids / metabolism*
Female
Gene Knockout Techniques
Humans
Immunologic Memory / drug effects*
Lymphocyte Activation / drug effects
Male
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / metabolism*
Oxidation-Reduction / drug effects
Oxidative Phosphorylation / drug effects
T-Lymphocytes, Regulatory / drug effects*
T-Lymphocytes, Regulatory / metabolism

Substances

Epoxy Compounds
Fatty Acids
CPT1B protein, mouse
Carnitine O-Palmitoyltransferase
Acacb protein, mouse
Acetyl-CoA Carboxylase
etomoxir

Abstract

Publication types

MeSH terms

Substances

Grants and funding