Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose tissue immune and metabolic tenors

Stromal sources of IL-33 in fat depots White adipose tissue (WAT) is home to Tregs and group 2 innate lymphoid cells (ILC2s) that help keep inflammation under check. Two studies in this week’s issue probe WAT in search of cells producing the alarmin cytokine IL-33 that regulates Tregs and ILC2s. Spallanzani et al. used single-cell RNA sequencing to characterize visceral WAT stromal cells and defined five distinct subtypes, with subtypes 1 to 3 producing IL-33 and subtypes 4 and 5 resembling adipocyte precursors. Mahlakõiv et al. identified adipose stem and progenitor cells as a source of IL-33 in all WAT depots and mesothelial cells as an additional source of IL-33 in visceral WAT. These studies improve our understanding of WAT stromal cell diversity and how the stromal cell landscape responds to physiological or pathological variations. See the related Research Article by Mahlakõiv et al. Regulatory T cells (Tregs) are key brakes on the visceral adipose tissue (VAT) inflammation that regulates local and systemic metabolic tenor. Breakdown of this regulation promotes type 2 diabetes. The cytokine IL-33 expands and sustains the unique Treg population residing within VAT. Here, relying on single-cell RNA sequencing, we identified the major IL-33 producers in VAT to be particular mesenchymal stromal cell subtypes, related to but distinct from adipocyte progenitor cells. We explored modulation of the VAT stromal cell landscape with physiologic variables such as age and sex, as well as its remodeling in pathogenic states like obesity. Last, we uncovered a VAT Treg:stromal cell negative regulatory loop that keeps the potent effect of IL-33 under rein. Adipose tissue Tregs dynamically dialogue with stromal cells via the ST2:IL-33 axis in homeostasis and disease. Adipose tissue Tregs dynamically dialogue with stromal cells via the ST2:IL-33 axis in homeostasis and disease.