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.

内脏脂肪组织（VAT）是一种能量储存和内分泌器官，对于代谢稳态至关重要。调节性 T (T _reg ) 细胞抑制炎症，以维持 VAT 稳态和葡萄糖耐量。在这里，我们发现 VAT 包含两种不同的 T _reg细胞群：典型的血清刺激 2 阳性 (ST2 ⁺ ) T _reg细胞，在男性中富集，以及先前未表征的 C–X–C 基序趋化因子受体 3 阳性 T reg 细胞群(CXCR3 ⁺ ) T _reg细胞在女性中丰富。我们发现转录因子 GATA 结合蛋白 3 和过氧化物酶体增殖物激活受体-γ 与细胞因子白细胞介素 33 一起促进 ST2 ⁺ VAT T _reg细胞的分化，但抑制 CXCR3 ⁺ T _reg细胞。相反，CXCR3 ⁺ T _reg细胞的分化是由细胞因子干扰素-γ 和转录因子 T-bet 介导的，它们也拮抗 ST2 ⁺ T _reg细胞。最后，我们证明 ST2 ⁺ T _reg细胞可维持葡萄糖稳态，而 CXCR3 ⁺ T _reg细胞可抑制瘦 VAT 中的炎症并防止高脂肪饮食条件下的葡萄糖不耐受。总体而言，这项研究定义了两种分子和发育上不同的 VAT T _reg细胞类型，具有独特的背景和性别特异性功能。