Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis
Saige L. Pompura, … , Margarita Dominguez-Villar, David A. Hafler
Saige L. Pompura, … , Margarita Dominguez-Villar, David A. Hafler
Published November 10, 2020
Citation Information: J Clin Invest. 2021;131(2):e138519. https://doi.org/10.1172/JCI138519.
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Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis

Abstract

FOXP3+ Tregs rely on fatty acid β-oxidation–driven (FAO-driven) oxidative phosphorylation (OXPHOS) for differentiation and function. Recent data demonstrate a role for Tregs in the maintenance of tissue homeostasis, with tissue-resident Tregs possessing tissue-specific transcriptomes. However, specific signals that establish tissue-resident Treg programs remain largely unknown. Tregs metabolically rely on FAO, and considering the lipid-rich environments of tissues, we hypothesized that environmental lipids drive Treg homeostasis. First, using human adipose tissue to model tissue residency, we identified oleic acid as the most prevalent free fatty acid. Mechanistically, oleic acid amplified Treg FAO–driven OXPHOS metabolism, creating a positive feedback mechanism that increased the expression of FOXP3 and phosphorylation of STAT5, which enhanced Treg-suppressive function. Comparing the transcriptomic program induced by oleic acid with proinflammatory arachidonic acid, we found that Tregs sorted from peripheral blood and adipose tissue of healthy donors transcriptomically resembled the Tregs treated in vitro with oleic acid, whereas Tregs from patients with multiple sclerosis (MS) more closely resembled an arachidonic acid transcriptomic profile. Finally, we found that oleic acid concentrations were reduced in patients with MS and that exposure of MS Tregs to oleic acid restored defects in their suppressive function. These data demonstrate the importance of fatty acids in regulating tissue inflammatory signals.

Authors

Saige L. Pompura, Allon Wagner, Alexandra Kitz, Jacob LaPerche, Nir Yosef, Margarita Dominguez-Villar, David A. Hafler

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Figure 2

Oleic acid increases the suppressive capacity of Tregs.

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Oleic acid increases the suppressive capacity of Tregs. (A) CFSE measure...
(A) CFSE measurement of the proliferation of Teffs cocultured with Tregs that were preincubated with vehicle, 10 μM oleic acid, 10 μM arachidonic acid, or 25 ng/mL IL-12 for 72 hours. Proliferation was measured after 4 days of coculture with Tregs (n = 10). Histograms are from 1 representative experiment. (B) Summary of the suppression data described in A based on 5 independent experiments. *P < 0.05 and **P < 0.01, by paired Student’s t test corrected for multiple-hypothesis testing using the Holm-Sidak method. (C) CFSE measurement of the proliferation of Teffs cocultured with Tregs that were preincubated with vehicle, 50 μM etomoxir, 10 μM oleic acid, or oleic acid plus etomoxir for 72 hours. Proliferation was measured after 4 days of coculture with Tregs (n = 8). Histograms are from 1 representative experiment. (D) Summary of suppression data at the 1:2 ratio. *P < 0.05 and **P < 0.01, by paired t test corrected for multiple-hypothesis testing using the Holm-Sidak method. Data represent the mean ± SEM.