Journal Article

Two regulatory T cell populations in the visceral adipose tissue shape systemic metabolism

Elmzzahi, Tarek, Prout, Melanie, Britt, Kara, Mason, Teisha, Shi, Wei, Wu, Jian, Malko, Darya, Abbott, Caitlin A., Torres, Santiago Valle, Pal, Bhupinder, Tsui, Carlson, McColl, Shaun R., Haynes, Vanessa, Hamada, Doaa, Chisanga, David, Groom, Joanna R., Beyer, Marc, Becker, Matthias, Kallies, Axel, Liao, Yang, Le Gros, Graham, Watt, Matthew J., Shakiba, Mehrnoush Hadaddzadeh, Vasanthakumar, Ajithkumar, Tang, Adelynn, Man, Kevin

2024

Overview

Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (T reg ) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct T reg cell populations: prototypical serum stimulation 2-positive (ST2 + ) T reg cells that are enriched in males and a previously uncharacterized population of C–X–C motif chemokine receptor 3-positive (CXCR3 + ) T reg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2 + VAT T reg cells but repress CXCR3 + T reg cells. Conversely, the differentiation of CXCR3 + T reg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2 + T reg cells. Finally, we demonstrate that ST2 + T reg cells preserve glucose homeostasis, whereas CXCR3 + T reg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT T reg cell types with unique context- and sex-specific functions. Here, the authors characterize two distinct T reg cell populations in the visceral adipose tissue of lean and high-fat diet-fed mice. ST2 + T reg cells are dominant in male mice and are transcriptionally driven by GATA3 and PPARγ, regulators that limit the differentiation of the more female-dominant population of CXCR3 + T reg cells that are T-bet dependent. Functional distinctions are also evident in glucose tolerance and adipose inflammation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/1619/554/1898/1271 / 631/250/256/2515 / 631/45 / Adipose tissue / Biomedical and Life Sciences / Biomedicine / Body fat / Cell differentiation / Chemokine receptors / CXCR3 protein / Cytokines / Female / GATA-3 protein / GATA-binding protein / Glucose / Glucose tolerance / High fat diet / Homeostasis / Humans / Immunological tolerance / Immunology / Infectious Diseases / Inflammation / Interleukin-1 Receptor-Like 1 Protein / Intra-Abdominal Fat / Lymphocytes T / Male / Peroxisome proliferator-activated receptors / T-Lymphocytes, Regulatory / Transcription factors / γ-Interferon