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) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct T cell populations: prototypical serum stimulation 2-positive (ST2) T cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3) T 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 cells but repress CXCR3 T cells. Conversely, the differentiation of CXCR3 T cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2 T cells. Finally, we demonstrate that ST2 T cells preserve glucose homeostasis, whereas CXCR3 T 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 cell types with unique context- and sex-specific functions.