Oleic acid Induces Tissue Resident FoxP3 Regulatory T cell Lineage Stability and Suppressive Functions

FoxP3 positive regulatory T cells (Tregs) rely on fatty acid oxidation (FAO)-driven OXPHOS for differentiation and function. Recent data have demonstrated a role for Tregs in the maintenance of tissue homeostasis with tissue-resident Tregs possessing tissue-specific transcriptomes. However, specific signals that establish these tissue-resident Tregs programs are largely unknown. As Tregs metabolically rely on FAO, and considering the lipid-rich environments of tissues, we hypothesized that environmental lipids drive Treg homeostasis. Using human adipose tissue as a model for tissue residency, we identify oleic acid as the most prevalent free fatty acid in human adipose tissue. Mechanistically, oleic acid amplifies Treg FAO-driven OXPHOS metabolism, creating a positive feedback mechanism that induces the expression of Foxp3 and enhances phosphorylation of STAT5, which acts to stabilize the Treg lineage and increase suppressive function. Comparing the transcriptomic program induced by oleic acid to that of the pro-inflammatory arachidonic acid, we find that Tregs sorted from peripheral blood and adipose of healthy donors transcriptomically resemble the oleic acid in vitro treated Tregs, whereas Tregs obtained from the adipose tissue of relapsing-remitting MS patients more closely resemble an arachidonic acid profile. Finally, we find that oleic acid concentrations are reduced in the fat tissue of MS patients, and exposure of dysfunctional MS Tregs to oleic acid restores defects in their suppressive function. These data demonstrate the importance of fatty acids in regulating tissue inflammatory signals.