Sex drives Tregs into fat

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Science Immunology  03 Apr 2020:
Vol. 5, Issue 46, eabb8620
DOI: 10.1126/sciimmunol.abb8620


Androgens promote inflammation in visceral adipose tissue (VAT), leading to the expansion of a distinct IL-33 producing stromal population and recruitment of Tregs.

Visceral adipose tissue (VAT) is not only an energy depot, but also an endocrine organ that regulates glucose metabolism. Obesity produces inflammation in VAT, which contributes to insulin resistance and type II diabetes. VAT-resident regulatory T cells (Tregs) have been shown to suppress adipose inflammation and preserve glucose metabolism. Given gender differences in adiposity and diabetes susceptibility across mammals, Vasanthakumar et al. set out to compare Tregs in VAT between male and female mice.

Male mice have increased Tregs in perigonadal VAT, but not other fat depots or tissues. Male VAT Tregs have higher expression of IL-33 receptor (ST2), KLRG1, CCR2, and the transcription factor BLIMP1. The expansion of male VAT Tregs is androgen dependent, and cells revert to a female phenotype in androgen receptor knockout mice (Ar–/–). Transfer of wild-type bone marrow into irradiated Ar–/– males also decreased Treg number, suggesting that the effect of sex hormones is Treg cell–extrinsic. To better characterize the tissue environment, the authors performed bulk RNA sequencing on total VAT, which included immune and stromal populations. Male VAT was enriched for proinflammatory markers TNFa, Il-6, Il-1b, and Ccl2 (the ligand for CCR2). Estrogen limits inflammation in females, with expression of these markers increasing to male levels in estrogen receptor knockout females. Additionally, NSAID treatment decreased VAT Tregs in males, suggesting that inflammation draws Tregs into the adipose. Male VAT is enriched for a CD73+ stromal population that produces IL-33. This CD73+ population is also androgen dependent, as it is largely absent in Ar–/– mice. Supplementing Ar–/– males with IL-33 restores Treg number, suggesting that the cytokine is limiting in adipose.

Taken together, the authors uncover a male-specific circuit in which androgens promote inflammation and the expansion of an IL-33–producing stromal cell population. Proinflammatory cytokines and IL-33 then recruit Tregs into male VAT. Treg expression of BLIMP1 produces a distinct Treg phenotype, and these cells may function to suppress inflammation and preserve glucose metabolism. Treg-specific deletion of Blimp1 worsens glucose tolerance in males. By contrast, estrogen limits VAT inflammation in females, eliminating the need to recruit Tregs.

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