A novel lineage of adipose tissue regulatory T cells controls obesity and insulin resistance

The epidemic of obesity and its associated systemic metabolic complications continues to increase. Adipose tissue (AT)-associated T cells have been proposed to play an important role in the regulation of bodyweight and insulin sensitivity with a link to Th1 or Th2 lineage specification. A specific subset of regulatory T cells (TREGS) plays a critical and non-redundant role in controlling systemic autoreactive immune responses. However, the lineage and functional role of TREGS found in AT (AT-TREGS) is undefined. Here we show that AT- TREGS comprise a distinct functional lineage. Remarkably, despite expressing a robust Th2 gene signature, AT-TREGS are predominantly derived from a precursor cell that had previously expressed the Th1 cell master regulator T-bet (Tbx21). This lineage relationship has profound functional consequences, as TREG- specific deletion of T-bet rendered mice completely resistant to diet induced obesity and insulin resistance. Mechanistically, T-bet directly suppresses ST2 (IL-33 receptor) expression, which renders Tregs less responsive to IL33-driven expression of amphiregulin in a cell-intrinsic manner. Our results identify a novel AT-selective TREG population with an unexpected lineage origin that determines the pathological response to a high fat intake. Understanding the upstream signals that regulate the survival and function of this cell-type may have profound relevance to the treatment of obesity and its associated disease, such as type II diabetes, cardiovascular disease, renal failure and stroke. Overall design: ChIP-seq to identify T-bet binding sites in murine Treg cells