Two regulatory T cell populations in the visceral adipose tissue shape systemic metabolism

Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (T reg ) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct T reg cell populations: prototypical serum stimulation 2-positive (ST2 + ) T reg cells that are enriched in males and a previously uncharacterized population of C–X–C motif chemokine receptor 3-positive (CXCR3 + ) T reg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2 + VAT T reg cells but repress CXCR3 + T reg cells. Conversely, the differentiation of CXCR3 + T reg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2 + T reg cells. Finally, we demonstrate that ST2 + T reg cells preserve glucose homeostasis, whereas CXCR3 + T reg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT T reg cell types with unique context- and sex-specific functions.