Adipose tissue regulatory T cells: differentiation and function

Abstract

Rising obesity levels, worldwide, are resulting in substantial increases in cardiovascular disease, diabetes, kidney disease, musculoskeletal disorders, and certain cancers, and obesity-associated illnesses are estimated to cause ∼4 million deaths worldwide per year. A common theme in this disease epidemic is the chronic systemic inflammation that accompanies obesity. CD4⁺ Foxp3⁺ regulatory T cells residing in visceral adipose tissues (VAT Tregs) are a unique immune cell population that play essential functions in restricting obesity-associated systemic inflammation through regulation of adipose tissue homeostasis. The distinct transcriptional program that defines VAT Tregs has been described, but directly linking VAT Treg differentiation and function to improving insulin sensitivity has proven more complex. Here we review new findings which have clarified how VAT Tregs differentiate, and how distinct VAT Treg subsets regulate VAT homeostasis, energy expenditure, and insulin sensitivity.

Keywords: Treg; adipose tissue; cytokine; thermogenesis.

Figure 1.

Cytokine maintenance and production by VAT Tregs. Graphic showing positive regulation of VAT Treg homeostasis by IL-33, TCR stimulation, and IL-2. Cytokine production by VAT Treg showing Csf1, Csf2, IL-10, and TNFα production by VAT Tregs and potential conversion of ATP/ADP to AMP and adenosine by CD39 and CD73 on the surface of the VAT Tregs. VAT Treg-derived IL-10 signaling represses Ucp1 and other thermogenic genes in adipocytes while adenosine helps to promote thermogenesis. VAT Treg-derived Csf1 and Csf2 may help recruit M2 macrophages to the VAT. TNFα can act as a proinflammatory cytokine on adipocytes and M1 macrophages. Figure created with BioRender.com.

Figure 2.

IL-33 stromal VAT cells and VAT Treg feedback. Graphic showing negative regulation of stromal VAT cell accumulation by VAT Tregs and IL-33 positive regulation of st2⁺ VAT Tregs by stromal VAT cells under standard fat diet (SFD) and high-fat diet (HFD). Figure and data based on Spallanzani et al. [42]. Figure created with BioRender.com.