Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis

J Clin Invest. 2021 Jan 19;131(2):e138519. doi: 10.1172/JCI138519.

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.

Keywords: Adipose tissue; Autoimmunity; Fatty acid oxidation; Immunology; Multiple sclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Female
  • Forkhead Transcription Factors / immunology*
  • Humans
  • Immune Tolerance / drug effects*
  • Male
  • Middle Aged
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / pathology
  • Oleic Acid / pharmacology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Oleic Acid