Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated Fatty Acid Oxidation
Raud B, Roy D, Divakaruni A, Tarasenko T, Franke R, Ma E, Samborska B, Hsieh W, Wong A, Stüve P, Arnold-Schrauf C, Guderian M, Lochner M, Rampertaap S, Romito K, Monsale J, Brönstrup M, Bensinger S, Murphy A, McGuire P, Jones R, Sparwasser T, Berod L
Published in
Cell metabolism: Volume 28, Issue 3, Page 504-515.e7
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.
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