292-OR: Treg Cells Control Systemic Lipid and Iron Metabolism via the OGT-STAT5 Axis

Abstract

Adipose tissue-resident regulatory T (Treg) cells have been proposed to exert metabolic roles in controlling inflammation, insulin sensitivity and thermogenesis. However, it is still largely unclear how Treg cells integrate immunological and metabolic signals to maintain systemic energy balance. Here we show that the glucose-sensitive O-linked N-Acetylglucosamine (O-GlcNAc) post-translational modification in Treg cells is activated by T cell receptor signaling. Through modifying the STAT5 protein and IL-2 signaling, protein O-GlcNAcylation supports the lineage stability and effector function of Treg cells, while loss of O-GlcNAc transferase (OGT) in Treg cells leads to systemic inflammation in mice. When fed with high fat diet, heterozygous Foxp3-OGT knockout females gain more fat mass as a result of reduced energy expenditure. On the other hand, constitutively active STAT5-mediated Treg-cell expansion and activation protect mice from diet-induced obesity and glucose intolerance. Mechanistically, Treg cells inhibit fatty acid uptake and regulate iron cycling in the adipose tissue. Taken together, we propose that the OGT-STAT5 axis enables Treg cells to maintain systemic lipid and iron homeostasis. Disclosure O.C. Salgado Barrero: None. H. Ruan: None. Funding American Diabetes Association (1-18-IBS-167 to H-B.R.); National Institutes of Health (R01AI139420)