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

Publication date: Available online 28 June 2018
Source:Cell Metabolism
Author(s): 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
T cell subsets including effector (Teff), regulatory (Treg), and memory (Tmem) 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⁺ Treg cell and Tmem 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 Teff, Tmem, or Treg 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 Tmem or Treg differentiation and suggest alternative mechanisms for the effects of etomoxir that involve mitochondrial respiration.

Graphical abstract

Teaser

Using genetic models of Cpt1a deficiency, Raud et al. demonstrate that long-chain fatty acid oxidation is largely dispensable for T cell activation and generation of CD8⁺ T memory (Tmem) cells and CD4⁺ Treg cells, and observe that, at high concentrations, the Cpt1 inhibitor etomoxir presents off-target effects on cell metabolism.


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