Obesity Contributes To A Dysfunctional Regulatory T Cell Phenotype Within Adipose Tissue

Adipose tissue (AT) regulatory T Cells (Tregs) play a key role in regulating inflammatory and metabolic responses. Obesity is associated with a decrease in AT Tregs as well as an increase in tissue inflammation and systemic insulin resistance in both humans and mice. We hypothesize that, in addition to the decrease in AT Treg number, there is a dysfunctional Treg phenotype caused by the increased inflammatory state within obese AT. We isolated Tregs from AT and peripheral blood(PB) from lean and obese individuals. Real-time PCR analysis was used to measure the expression of several known markers for T cell exhaustion. Protein expression of each marker was validated using FACS analysis. When compared to PB, there was a significant increase in PD-1 expression on AT Tregs. PD-1 and TIGIT were increased in Tregs isolated from obese vs. lean individuals, while CD127 expression was reduced. To determine if PD-1 expression correlates with Treg dysfunction, isolated AT and PB Tregs were added to CFSE-labeled PBMC. After 4 days culture, PB Tregs significantly inhibited proliferation but there was less suppression by AT Tregs. RNAseq analyses of PD-1 high vs. PD-1 negative AT and PB Tregs revealed a unique expression phenotype within AT Tregs. AT PD-1 high Tregs express altered metabolic and inflammatory pathways promoting loss of Tregs and increased inflammation. These data suggest that Treg exhaustion may explain the decreased Treg abundance in AT of obese individuals, which has important metabolic implications. (Partially supported by Foods for Health, a focus area of the Discovery Themes Initiative at The Ohio State University)