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Πέμπτη 28 Ιουνίου 2018

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

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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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