The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue–resident regulatory T cells

Abstract

Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.

IL-33 Reverses an Obesity-Induced Deficit in Visceral Adipose Tissue ST2+ T Regulatory Cells and Ameliorates Adipose Tissue Inflammation and Insulin Resistance

“…Our data are consistent with a recent report that the majority of VAT-resident Tregs express ST2, and IL-33 treatment promoted the increase of VAT Tregs, reduced VAT inflammation, and improved glucose tolerance of HFD mice (37). In addition, we show that DIO diminishes ST2…”

Obesity-Associated Adipose Tissue Inflammation and Transplantation

“…Specifically, AT Tregs express elevated levels of IL-10, GATA3, CCR4, and the ST2 chain of the IL-33 receptor. The expression of all of these proteins on Tregs is diminished in obese AT (19)(20)(21)(22)(23). Diphtheria toxinmediated depletion of Tregs results in AT inflammation and insulin resistance (19), indicating that Tregs have a key role in maintaining metabolic homeostasis.…”

“…Diphtheria toxinmediated depletion of Tregs results in AT inflammation and insulin resistance (19), indicating that Tregs have a key role in maintaining metabolic homeostasis. The unique phenotype of AT Tregs seems to be driven at least partly by IL-33, because the administration of exogenous IL-33 induces proliferation in AT Tregs, restores their classic Th2-like phenotype, and is sufficient to resolve obesity-associated AT inflammation (21)(22)(23). The question of whether the effects of IL-33 on Tregs are direct or indirect, however, requires further research because IL-33 also has major effects on eosinophils and ILC2s, which could feed back and result in the observed change in Treg phenotype (15).…”

Unstable FoxP3 + T regulatory cells in NZW mice

“…Cytokines-IL-2 foremost-are thought to be the main controllers of Treg proportions and numbers (15)(16)(17)(18)(19)(20)(21)(22), although the relative importance of these controllers varies with location and subphenotype [e.g., the alarmin IL-33 has a more profound role in tissue Tregs (21)(22)(23)]. Perhaps surprisingly, in light of this apparently tight control, there is a wide range of variation in Treg proportions, with several studies having observed up to fourfold variation in the blood of healthy humans (e.g., refs.…”