Inflammation-dependent differentiation of two distinct regulatory T cell populations in the visceral adipose tissue shapes systemic metabolism [RNA-seq II]

Visceral adipose tissue (VAT) is an endocrine organ critical for energy storage and metabolic homeostasis. Its function, at least in part, is controlled by immune cells, including Foxp3+ regulatory T (Treg) cells, which restrain VAT inflammation and glucose intolerance. Here we uncover that the VAT harbours two distinct Treg cell populations, prototypical ST2+ Treg cells, that are enriched in males and depend on the cytokine IL-33 and the transcription factor PPAR and a previously uncharacterized population of VAT Treg cells that express the chemokine receptor CXCR3+, are enriched in females and depend on the transcription factor T-bet. We further show that the transcription factor GATA3 promoted differentiation of ST2+ VAT Treg cells and together with PPAR and IL-33 repressed the differentiation of CXCR3+ Treg cells. CXCR3+ VAT Treg cells developed from naïve Treg cells in a cytokine IFN- dependent manner. Finally, we demonstrate that ST2+ Treg cells promoted glucose tolerance, while CXCR3+ Treg cells limited VAT inflammation in a sex specific manner. This study for the first time establishes how inflammation determines the developmental trajectories of two functionally and molecularly distinct Treg cell types in the VAT. Bulk RNA sequencing of VAT Treg cells obtained from male and female wildtype, Gata3KO and Tbet KO mice. In the KO mice, Gata3 and Tbet transcription factors are ablated in a Treg specific manner using Foxp3Cre