Sex-specific adipose tissue imprinting of regulatory T cells

Ajithkumar Vasanthakumar (), David Chisanga, Jonas Blume, Renee Gloury, Kara Britt, Darren C. Henstridge, Yifan Zhan, Santiago Valle Torres, Sebastian Liene, Nicholas Collins, Enyuan Cao, Tom Sidwell, Chaoran Li, Raul German Spallanzani, Yang Liao, Paul A. Beavis, Thomas Gebhardt, Natalie Trevaskis, Stephen L. Nutt, Jeffrey D. Zajac, Rachel A. Davey, Mark A. Febbraio, Diane Mathis, Wei Shi and Axel Kallies ()
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Ajithkumar Vasanthakumar: University of Melbourne
David Chisanga: The Walter and Eliza Hall Institute of Medical Research
Jonas Blume: University of Melbourne
Renee Gloury: University of Melbourne
Kara Britt: Peter MacCallum Cancer Centre
Darren C. Henstridge: University of Tasmania
Yifan Zhan: The Walter and Eliza Hall Institute of Medical Research
Santiago Valle Torres: University of Melbourne
Sebastian Liene: University of Melbourne
Nicholas Collins: University of Melbourne
Enyuan Cao: Monash Institute of Pharmaceutical Sciences
Tom Sidwell: University of Melbourne
Chaoran Li: Harvard Medical School
Raul German Spallanzani: Harvard Medical School
Yang Liao: The Walter and Eliza Hall Institute of Medical Research
Paul A. Beavis: Peter MacCallum Cancer Centre
Thomas Gebhardt: University of Melbourne
Natalie Trevaskis: Monash Institute of Pharmaceutical Sciences
Stephen L. Nutt: The Walter and Eliza Hall Institute of Medical Research
Jeffrey D. Zajac: The University of Melbourne
Rachel A. Davey: The University of Melbourne
Mark A. Febbraio: Monash Institute of Pharmaceutical Sciences
Diane Mathis: Harvard Medical School
Wei Shi: The Walter and Eliza Hall Institute of Medical Research
Axel Kallies: University of Melbourne

Nature, 2020, vol. 579, issue 7800, 581-585

Abstract: Abstract 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 VAT7–9. Here we uncover pronounced sexual dimorphism in Treg cells in the VAT. Male VAT was enriched for Treg cells compared with female VAT, and Treg 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 Treg 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 Treg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident Treg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in Treg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.

Date: 2020
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DOI: 10.1038/s41586-020-2040-3

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