Integrated transcriptional and chromatin accessibility profiling uncovers sex-specific adipose tissue imprinting of regulatory T cells

David Chisanga0, Ajith Vasanthakumar1, Wei Shi0, Axel Kallies1
(0) Olivia Newton-John Cancer Research Institute
(1) University of Melbourne

Find me on Wed Nov 25th, 1:30-2:50pm AEDT in Remo, table 134

Abstract
Integrated transcriptional and chromatin accessibility profiling reveals sex-specific adipose tissue imprinting of regulatory T cells

Adipose tissue, commonly referred to as body fat is a dynamic endocrine organ whose main function is as an energy repository together with cushioning and insulating the body. Especially, visceral adipose tissue (VAT) is critical for the regulation of systemic energy homeostasis by acting as a caloric reservoir. Therefore, the impairment of VAT function like in obesity is associated with insulin resistance and type 2 diabetes. Regulatory T (Treg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT.
Differences between sexes with respect to the physiology and organismal metabolism in adipose tissue are well documented across species. Here, we integrated transcriptome (RNA-seq) and chromatin accessibility (ATAC-seq) datasets to uncover distinct sexual dimorphism in Treg cells in the VAT. Our results showed that VAT in males was enriched for Treg cells in comparison to VAT in females, and Treg cells from VAT in males were strikingly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Furthermore, increased inflammation in the VAT in males 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.

References
Vasanthakumar, A., Chisanga, D., Blume, J. et al. Sex-specific adipose tissue imprinting of regulatory T cells. Nature 579, 581–585 (2020). https://doi.org/10.1038/s41586-020-2040-3