Adipose tissue regulatory T cells: differentiation and function.

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.

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis.

Interleukin-10 (IL-10) is a critical cytokine used by immune cells to suppress inflammation. Paradoxically, immune cell-derived IL-10 can drive insulin resistance in obesity by suppressing adipocyte energy expenditure and thermogenesis. However, the source of IL-10 necessary for the suppression of adipocyte thermogenesis is unknown. We show here that CD4+Foxp3+ regulatory T cells (Tregs) are a substantial source of IL-10 and that Treg-derived IL-10 can suppress adipocyte beiging. Unexpectedly, Treg-specific loss of IL-10 resulted in increased insulin sensitivity and reduced obesity in high-fat diet-fed male mice. Mechanistically, we determined that Treg-specific loss of the transcription factor Blimp-1, a driver of IL-10 expression by Tregs, phenocopied the Treg-specific IL-10-deficient mice. Loss of Blimp-1 expression in Tregs resulted in reduced ST2+KLRG1+, IL-10-secreting Tregs, particularly in the white adipose tissue. Blimp-1-deficient mice were protected from glucose intolerance, insulin resistance, and diet-induced obesity, through increased white adipose tissue browning. Taken together, our data show that Blimp-1-regulated IL-10 secretion by Tregs represses white adipose tissue beiging to maintain adipose tissue homeostasis.

The Transcriptional Regulator Id2 Is Critical for Adipose-Resident Regulatory T Cell Differentiation, Survival, and Function.

Adipose regulatory T cells (aTregs) have emerged as critical cells for the control of local and systemic inflammation. In this study, we show a distinctive role for the transcriptional regulator Id2 in the differentiation, survival, and function of aTregs in mice. Id2 was highly expressed in aTregs compared with high Id3 expression in lymphoid regulatory T cells (Tregs). Treg-specific deletion of Id2 resulted in a substantial decrease in aTregs, whereas Tregs in the spleen and lymph nodes were unaffected. Additionally, loss of Id2 resulted in decreased expression of aTreg-associated markers, including ST2, CCR2, KLRG1, and GATA3. Gene expression analysis revealed that Id2 expression was essential for the survival of aTregs, and loss of Id2 increased cell death in aTregs due to increased Fas expression. Id2-mediated aTreg depletion resulted in increased systemic inflammation, increased inflammatory macrophages and CD8+ effector T cells, and loss of glucose tolerance under standard diet conditions. Thus, we reveal an unexpected and novel function for Id2 in mediating differentiation, survival, and function of aTregs that when lost result in increased metabolic perturbation.

The Lysophosphatidylcholine Transporter MFSD2A Is Essential for CD8+ Memory T Cell Maintenance and Secondary Response to Infection.

Access to nutrients is critical for an effective T cell immune response to infection. Although transporters for sugars and amino acids have previously been described in the context of the CD8+ T cell immune response, the active transport of exogenous fatty acids has remained enigmatic. In this study, we discovered that the sodium-dependent lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain containing 2A (MFSD2A) is upregulated on activated CD8+ T cells and is required for memory T cell maintenance. MFSD2A deficiency in mice resulted in decreased import of LPC esterified to long chain fatty acids into activated CD8+ T cells, and MFSD2A-deficient cells are at a competitive disadvantage resulting in reduced memory T cell formation and maintenance and reduced response to secondary infection. Mechanistically, import of LPCs was required to maintain T cell homeostatic turnover, which when lost resulted in a decreased memory T cell pool and thus a reduced secondary response to repeat infection.

TGF-ß1-induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic antigen-mediated disease characterized by esophageal eosinophilia, remodeling, and fibrosis. TGF-ß1 is a central regulator of EoE remodeling and increases esophageal smooth muscle (ESM) cell contraction. OBJECTIVE: In this study we aimed to understand the molecular mechanisms by which TGF-ß1 could induce ESM cell contraction. METHODS: We used primary human ESM cells and esophageal myofibroblasts (EMFs) to assess the mechanisms of TGF-ß1-induced contraction. We analyzed the expression, phosphorylation, and function of phospholamban (PLN), a sarcoendoplasmic reticulum regulatory protein induced by TGF-ß1. Expression of PLN, phospho-PLN, and its regulatory pathway was analyzed in the ESM of biopsy specimens from patients with EoE and control subjects. Gene silencing in EMFs from patients with EoE was used to understand the role of PLN in contraction. RESULTS: TGF-ß1 induced and phosphorylated PLN in primary human ESM cells and EMFs from patients with EoE. PLN and phospho-PLN levels were increased in smooth muscle from patients with EoE compared with that seen in smooth muscle from control subjects in vivo. PLN inhibition significantly diminished TGF-ß1-induced EMF contraction in patients with EoE. PLN expression and ESM/EMF contraction depended on TGF-ß receptor I signals. CONCLUSION: We describe a previously unrecognized mechanism for ESM cell contraction that depends on TGF-ß1, its receptors, and PLN. Because PLN levels are increased in smooth muscle from patients with EoE and PLN silencing diminishes contraction, we provide a novel potential mechanistic framework and therapeutic target for ESM dysfunction in patients with EoE.

Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a clinicopathologic entity of increasing worldwide prevalence. IL-5 is essential for eosinophil trafficking, and anti-IL-5 therapy decreases esophageal eosinophilia. EoE is associated with prominent mast cell infiltration. OBJECTIVE: We investigated whether anti-IL-5 (mepolizumab) treatment reduced esophageal mast cell accumulation in biopsy specimens from pediatric patients with EoE from a previous randomized anti-IL-5 trial. METHODS: A subanalysis was completed for children treated with 0.55, 2.5, or 10 mg/kg mepolizumab monthly for 12 weeks followed by no treatment until week 24. Quantitative immunochemistry was used to assess the numbers of eosinophils, tryptase-positive mast cells, IL-9(+) cells, and mast cell-eosinophil couplets before and after treatment. RESULTS: Forty-three biopsy specimens had adequate tissue for paired analysis. Forty percent of subjects responded to anti-IL-5 (defined as <15 eosinophils per high-power field [hpf] after mepolizumab therapy), and 77% of all subjects had decreased numbers of mast cells after anti-IL-5. In responders epithelial mast cell numbers decreased from 62 to 19 per hpf (P < .001), were significantly lower than in nonresponders after therapy (P < .05), and correlated with eosinophil numbers (r = 0.75, P < .0001). Mast cells and eosinophils were found in couplets before therapy, and these were significantly decreased only in responders after anti-IL-5 (P < .001). Esophageal eosinophils comprised the majority of cells that made the mast cell growth factor IL-9. IL-9(+) cell numbers decreased from 102 to 71 per hpf (P < .001) after anti-IL-5. CONCLUSIONS: Pediatric patients with EoE had significantly fewer mast cells, IL-9(+) cells, and mast cell-eosinophil couplets in the esophageal epithelium after anti-IL-5 therapy. Because eosinophils were one source of IL-9, they might support esophageal mastocytosis.