Adipose tissue-resident regulatory T cells: phenotypic specialization, functions and therapeutic potential

Abstract

Foxp3(+) CD4(+) regulatory T (Treg) cells, recognized to be one of the most important defences of the human body against an inappropriate immune response, have recently gained attention from those outside immunology thanks to the compelling evidence for their capability to exert non-canonical immune functions in a variety of tissues in health and disease. The recent discovery of the differences between tissue-resident Treg cells and those derived from lymphoid organs is affecting the mindset of many investigators now questioning the broad applicability of observations originally based on peripheral blood/lymphoid organ cells. So far, the best characterized 'Treg flavour' comes from studies focused on their role in suppressing adipose tissue inflammation and obesity-driven insulin resistance. Adipose tissue derived Treg cells are distinct from their counterparts in lymphoid organs based on their transcriptional profile, T-cell receptor repertoire, and cytokine and chemokine receptor expression pattern. These cells are abundant in visceral adipose tissue of lean mice but their number is greatly reduced in insulin-resistant animal models of obesity. Interestingly, peroxisome-proliferator-activated receptor γ expression by visceral adipose tissue Treg cells is crucial for their accumulation, phenotype and function in the fat and surprisingly necessary for complete restoration of insulin sensitivity in obese mice by the anti-diabetic drug Pioglitazone. This review surveys recent findings relating to the unique phenotype and function of adipose tissue-resident Treg cells, speculates on the nature of their dynamics in lean and obese mouse models, and analyses their potential therapeutic application in the treatment of type 2 diabetes.

Keywords: adipose tissue; obesity; peroxisome-proliferator-activated receptor γ; regulatory T cells; type 2 diabetes.

Figure 1

Cellular and metabolic balance in adipose tissue. In lean mice, visceral adipose tissue (VAT) is enriched by anti-inflammatory macrophages (M2 MΦ), and regulatory T (Treg) cells. In contrast, in obese mice, there is a switch in cellular equilibrium: fewer Treg cells and a predominance of pro-inflammatory macrophages (M1 MΦ). The anti-diabetic drug, Pioglitazone, which is a synthetic Peroxisome-proliferator-activated receptor γ (PPARγ) ligand, and anti-CD3-monoclonal antibody treatment boost the accumulation of Treg cells and reduces the infiltration of M1 MΦ in VAT of obese mice. Similarly, obese mouse treatment with either Metformin, or interleukin-2 (IL-2) complexes, increases VAT Treg cells although their effect on the modulation of M1 MΦ remains uncharacterized. Strikingly, obese mice, carrying the specific deficiency of PPARγ in Treg cells do not accumulate VAT Treg cells and consequently respond only partially to Pioglitazone treatment. Obese female mice, which are historically known to be protected from high-fat diet-induced insulin resistance, are enriched by M2 MΦ and Treg cells. Early stages of weight loss and fasting are marked by a rapid recruitment of anti-inflammatory macrophages to VAT in response to lipolysis. Macrophage infiltration is instead reduced in VAT of patients which have undergone gastric bypass surgery for weight loss. However, this observation was made 3 months after bariatric surgery and provides only a late snapshot of MΦ phenotypes in VAT. The effect of caloric restriction and/or bariatric surgery on Treg dynamics in adipose tissue remains to be addressed and represents an interesting opportunity to verify the inverse correlation between Treg cell numbers and insulin resistance.