Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Nature. 2020 Mar;579(7800):581-585. doi: 10.1038/s41586-020-2040-3. Epub 2020 Feb 26.
Adipose tissue is an energy store and a dynamic endocrine organ. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes. Regulatory T (T) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT. Here we uncover pronounced sexual dimorphism in T cells in the VAT. Male VAT was enriched for T cells compared with female VAT, and T cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of T cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of T cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident T cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in T cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.
脂肪组织既是能量储存库，也是一个活跃的内分泌器官。特别是内脏脂肪组织（VAT）对于全身代谢的调节至关重要。VAT 功能受损——例如在肥胖症中——与胰岛素抵抗和 2 型糖尿病有关。表达转录因子 FOXP3 的调节性 T（T）细胞对于限制免疫反应和抑制组织炎症（包括 VAT 中的炎症）至关重要。在这里，我们揭示了 VAT 中的 T 细胞存在明显的性别二态性。与女性 VAT 相比，男性 VAT 中富含 T 细胞，而且男性 VAT 中的 T 细胞在表型、转录图谱和染色质可及性方面与女性 VAT 中的 T 细胞明显不同。男性 VAT 中的炎症加剧促进了 T 细胞通过 CCL2-CCR2 轴的募集。雄激素调节一种独特的、仅存在于男性 VAT 中的 IL-33 产生基质细胞群体的分化，这与 T 细胞的局部扩增相平行。性激素还调节 VAT 炎症，以 BLIMP1 转录因子依赖性的方式塑造 VAT 驻留 T 细胞的转录图谱。总的来说，我们发现 VAT 中的 T 细胞的性别特异性差异是由组织小生境以依赖于性激素的方式决定的，以限制脂肪组织炎症。
