Characterization of regulatory T cells in obese omental adipose tissue in humans

Abstract

Obesity-associated visceral adipose tissue (AT) inflammation promotes insulin resistance and type 2 diabetes (T2D). In mice, lean visceral AT is populated with anti-inflammatory cells, notably regulatory T cells (Tregs) expressing the IL-33 receptor ST2. Conversely, obese AT contains fewer Tregs and more proinflammatory cells. In humans, however, there is limited evidence for a similar pattern of obesity-associated immunomodulation. We used flow cytometry and mRNA quantification to characterize human omental AT in 29 obese subjects, 18 of whom had T2D. Patients with T2D had increased proportions of inflammatory cells, including M1 macrophages, with positive correlations to body mass index. In contrast, Treg frequencies negatively correlated to body mass index but were comparable between T2D and non-T2D individuals. Compared to human thymic Tregs, omental AT Tregs expressed similar levels of FOXP3, CD25, IKZF2, and CTLA4, but higher levels of PPARG, CCR4, PRDM1, and CXCL2. ST2, however, was not detectable on omental AT Tregs from lean or obese subjects. This is the first comprehensive investigation into how omental AT immunity changes with obesity and T2D in humans, revealing important similarities and differences to paradigms in mice. These data increase our understanding of how pathways of immune regulation could be targeted to ameliorate AT inflammation in humans.Keywords: Adipose tissue r IL-33 r Immune regulation r Metabolism r Regulatory T cells (Tregs) r Type 2 diabetes (T2D) Additional supporting information may be found online in the Supporting Information section at the end of the article.

Immunometabolism: From basic mechanisms to translation

“…In addition to macrophages, a unique visceral fat—specific Treg population was recently defined that functions to keep this vast depot of adipose tissue quiescent in terms of inflammation to maximally sensitize insulin signaling 69,70 . A review by Li and Spallanzani et al details a critical role of visceral adipose tissue (VAT) mesenchymal stromal cells (VmSCs) in regulating VAT Tregs, local, and systemic inflammation in obesity 71 .…”

Type 2 Diabetes: How Much of an Autoimmune Disease?

“…Patients with T2D had increased proportions of inflammatory cells, including M1 macrophages, with positive correlations to BMI. Treg frequencies did negatively correlate with BMI but were similar in T2D and non-T2D subjects (118). Compared to thymic population, omental AT Treg cells expressed higher levels of PPAR-γ, but failed to show any detectable expression of IL-33 receptor, ST2 (118), thus contradicting a previous report (112).…”

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

“…We also provide some tips in Table for staining additional human Treg markers that are not specifically included in the protocols outlined and highlight some key differences between mouse and peripheral human Tregs. The reader is also referred to our previously published methods for staining human Tregs within omental adipose tissue , thymus tissue and using a mass cytometry platform , as well as a review describing a comprehensive comparison of mouse and human Treg markers . The methods described here are focused on studying Tregs in healthy subjects.…”