Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis
Saige L. Pompura, Allon Wagner, Alexandra Kitz, Jacob LaPerche, Nir Yosef, Margarita Dominguez-Villar, David A. Hafler
Saige L. Pompura, Allon Wagner, Alexandra Kitz, Jacob LaPerche, Nir Yosef, Margarita Dominguez-Villar, David A. Hafler
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Research Article Autoimmunity Immunology

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 6

Oleic acid partially negates the MS Treg proinflammatory phenotype.

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Oleic acid partially negates the MS Treg proinflammatory phenotype. (A)...
(A) Representative dot plot of healthy donor or MS Tregs sorted from frozen PBMCs and stimulated in the presence or absence of 10 μM oleic acid or arachidonic acid for 72 hours. Intracellular staining for IFN-γ (top) or IL-10 (bottom) was measured after a 4-hour stimulation with PMA and ionomycin in the presence of GolgiStop. (B) Summary of IFN-γ+ and IL-10+ healthy and MS Tregs after treatment with 10 M oleic acid or arachidonic acid for 3 days (n = 8). *P < 0.05 and **P < 0.01, by paired Student’s t test corrected for multiple-hypothesis testing using the Holm-Sidak method. (C) mRNA expression of the indicated genes relative to control, measured in the healthy and MS Tregs described in A (n = 10). *P < 0.05 and **P < 0.01, by paired Student’s t test corrected for multiple-hypothesis testing using the Holm-Sidak method. (D) Mass spectrometric analysis of LCFAs in supernatant from human adipose tissue samples compared with blood plasma of healthy donors or patients with MS (n = 6) *P < 0.05, **P < 0.01, and ***P < 0.001, by paired Student’s t test corrected for multiple-hypothesis testing using the Holm-Sidak method. Data represent the mean ± SEM.