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Foxp3 drives oxidative phosphorylation and protection from lipotoxicity
Duncan Howie, … , Alexander G. Betz, Herman Waldmann
Duncan Howie, … , Alexander G. Betz, Herman Waldmann
Published February 9, 2017
Citation Information: JCI Insight. 2017;2(3):e89160. https://doi.org/10.1172/jci.insight.89160.
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Research Article Immunology Metabolism

Foxp3 drives oxidative phosphorylation and protection from lipotoxicity

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Abstract

Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation–fueled oxidative phosphorylation (OXPHOS). It is unclear why this form of metabolism is favored in Tregs and, more specifically, whether this program represents an adaptation to the environment and developmental cues or is “hardwired” by Foxp3. Here we show, using metabolic analysis and an unbiased mass spectroscopy–based proteomics approach, that Foxp3 is both necessary and sufficient to program Treg-increased respiratory capacity and Tregs’ increased ability to utilize fatty acids to fuel oxidative phosphorylation. Foxp3 drives upregulation of components of all the electron transport complexes, increasing their activity and ATP generation by oxidative phosphorylation. Increased fatty acid β-oxidation also results in selective protection of Foxp3+ cells from fatty acid–induced cell death. This observation may provide novel targets for modulating Treg function or selection therapeutically.

Authors

Duncan Howie, Stephen Paul Cobbold, Elizabeth Adams, Annemieke Ten Bokum, Andra Stefania Necula, Wei Zhang, Honglei Huang, David J. Roberts, Benjamin Thomas, Svenja S. Hester, David J. Vaux, Alexander G. Betz, Herman Waldmann

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Figure 5

Foxp3 expression enhances expression of electron transport system proteins.

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Foxp3 expression enhances expression of electron transport system protei...
(A) Foxp3 expression experiments for proteomic analysis. Cell comparisons used to quantitate proteomic differences between Foxp3+ and Foxp3– cells. (B) Electron transport system protein subunit comparison between Foxp3 positive and negative T cells. Red boxes indicate proteins with a Foxp3+/Foxp3– ratio in the 75th percentile of all proteins measured. Green boxes indicate proteins with a Foxp3+/Foxp3– ratio in the 25th percentile of all measured proteins. Yellow boxes indicate proteins with no change between Foxp3+ or Foxp3–. White boxes indicate proteins not present in the proteome. Figure adapted from http://wikipathways.org/index.php/Pathway:WP295. (C) Gene set enrichment analysis of the mass spectroscopy data from experiments 1–3. NES, normalized enrichment score. P values calculated using a weighted Kolmogorov-Smirnov test. (D) Flow cytometric measurement of ATP5a, NDUFA9, and SDHA on permeabilized splenic CD4+CD2– and CD4+CD2+ cells from C57BL/6.foxp3hCD2 knockin mice. Data representative of 2 separate experiments.

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