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Sex-specific adipose tissue imprinting of regulatory T cells.

ABSTRACT: 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.

SUBMITTER: Vasanthakumar A

PROVIDER: S-EPMC7241647 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Sex-specific adipose tissue imprinting of regulatory T cells.

Vasanthakumar Ajithkumar A Chisanga David D Blume Jonas J Gloury Renee R Britt Kara K Henstridge Darren C DC Zhan Yifan Y Torres Santiago Valle SV Liene Sebastian S Collins Nicholas N Cao Enyuan E Sidwell Tom T Li Chaoran C Spallanzani Raul German RG Liao Yang Y Beavis Paul A PA Gebhardt Thomas T Trevaskis Natalie N Nutt Stephen L SL Zajac Jeffrey D JD Davey Rachel A RA Febbraio Mark A MA Mathis Diane D Shi Wei W Kallies Axel A

Nature 20200226 7800

Adipose tissue is an energy store and a dynamic endocrine organ1,2. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism3,4. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes5,6. Regulatory T (Treg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT7- ...[more]

PMID: 32103173

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Project description:The prevalence of cardiovascular disease has increased among middle-aged women in the United States, yet has declined in middle-aged men. In experimental stroke, middle-aged females have larger strokes and greater inflammation than age-matched males or younger females. The mechanism underlying this shift from an "ischemia-protected" to an "ischemia-sensitive" phenotype in aging females is unknown. One potential factor is an age-related increase in systemic factors that induce inflammation. Increased abdominal fat deposition is seen in women during middle age. Adipose tissue plays a key role in obesity-induced systemic inflammation, including increased pro-inflammatory cytokines. We hypothesized that age and sex differences in adipose immune cells promote an augmented pro-inflammatory milieu in middle-aged females driven by a balance shift between pro-inflammatory and anti-inflammatory T cells. Abdominal adipose tissue immune cells from young (3-4?months) and middle-aged (15-16?months) male and female C57BL/6J mice were analyzed by flow cytometry. Plasma triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were determined with colorimetric assays. Middle-aged mice had higher adipose tissue mass compared to young mice. Lipid profiling showed no sex differences in TG and LDL, but middle-aged females had lower HDL (0.84?±?0.07??g/?l) than middle-aged males (1.35?±?0.06??g/?l). Flow cytometry data demonstrated an age-associated increase in adipose tissue CD8+ T cells that was augmented by female sex, with middle-aged females having a higher percentage of CD8+ cells (34.4?±?3.2% of CD3+ T cells) than middle-aged males (24.4?±?2.2%). This increase in CD8+ T-cell proportion was adipose tissue-specific, as this change was not observed in blood. Middle-aged females had higher numbers of activated (CD69+) CD8+ T cells than males. In addition, female CD8+ T cells produced higher levels of IFN-?, TNF-?, and granzyme B ex vivo, and females had higher adipose levels of IFN-?, RANTES and MIP-1? than middle-aged males. In parallel, females had lower levels of regulatory T cells (Tregs), an anti-inflammatory T-cell subtype, compared to age-matched males. In conclusion, middle-aged females have a detrimental combination of elevated pro-inflammatory T cells and decreased anti-inflammatory Tregs in adipose tissue, which may promote a pro-inflammatory milieu and contribute to increased cardiovascular disease burden in aging females.

Dataset Information

Sex-specific adipose tissue imprinting of regulatory T cells.

Publications

Sex-specific adipose tissue imprinting of regulatory T cells.

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