Sex-specific adipose tissue imprinting of regulatory T cells

Adipose tissue is an energy store and a dynamic endocrine organ^1,2. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism^3,4. Impaired VAT function—for example, in obesity—is associated with insulin resistance and type 2 diabetes^5,6. Regulatory T (T_reg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT^7–9. Here we uncover pronounced sexual dimorphism in T_reg cells in the VAT. Male VAT was enriched for T_reg cells compared with female VAT, and T_reg 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_reg 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_reg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident T_reg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in T_reg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.