Interferon-α-producing plasmacytoid dendritic cells drive the loss of adipose tissue regulatory T cells during obesity

The visceral adipose tissue (VAT) of lean mice hosts a unique population of regulatory T cells (Tregs) that have a distinct transcriptome and T cell receptor (TCR) repertoire and regulate local and systemic inflammation and metabolism. Perplexingly, this population disappears in obese mice, limiting the promise of Treg-based therapies for metabolic disorders. We exploited the power of a VAT-Treg TCR-transgenic mouse model to follow the dynamics of, and phenotypic changes in, the VAT-Treg population throughout the development of diet-induced obesity. Our results show that VAT-Tregs are lost under obesogenic conditions due to downregulation of their defining transcription factor, PPARγ, coupled with their strikingly enhanced responses to pro-inflammatory cytokines. In particular, the VAT from obese mice (and reportedly humans) was strongly enriched in plasmacytoid dendritic cells that actively express interferon-alpha. These cells were directly toxic to PPARγ⁺ VAT-Tregs. Blocking this pathway in obese mice by multiple approaches substantially restored the VAT-Treg population and enhanced insulin sensitivity.