Regulatory T (Treg) cells dampen immune responses to avoid excessive, deleterious inflammation in the context of autoimmunity, allergy, and infection. Treg cells also impede anti-tumor immunity. Therefore, modulation of Treg cell activity is of great therapeutic potential for treating many debilitating inflammatory diseases and cancer. Recent studies have suggested that in addition to their prominent immunosuppressive function, Treg cells have a distinct and non-redundant role in tissue maintenance and remodeling. These Treg cells exhibit a unique transcriptional signature represented by high expression of the EGF family member amphiregulin (Areg). Importantly, tumor infiltrating Treg cells highly express Areg. Since Areg is known to exert pleiotropic oncogenic activities, Areg producing Treg cells may be crucial for establishing the tumor microenvironment. It has been increasingly appreciated that lymphocyte activation and differentiation are coupled to specific metabolic pathways. Metabolic reprogramming is dictated by cytokine and growth factor signals, as well as the availability of nutrients. In addition, metabolic products provide substrates that can alter the functional status of a cell through posttranslational modifications (PTMs). Among the various nutrients, glucose is a key metabolic substrate for T cells. Aerobic glycolysis in activated T cells is required for the acquisition of full effector function. Treg cells in the secondary lymphoid organs and the tissue have distinct glucose availability and metabolic needs. We thus hypothesized that glucose sensing and glucose metabolism play essential roles in shaping the unique phenotype and function of tissue resident Treg cells. O-linked GlcNAcylation is a PTM dynamically regulated by glucose levels and controls the function of many proteins, including transcription factors that play key roles in T cell activation such as NF-κB, CREB, and NFAT. To understand the mechanism by which glucose metabolism controls the function of tissue-resident Treg cells, we began to characterize protein O-GlcNAcylation in Treg cells, and found that both human and mouse Foxp3, the master regulator transcription factor of Treg cells, undergoes O-GlcNAcylation. We are in the process of mapping the site of O-GlcNAcylation of Foxp3, and understanding the physiological significance of this PTM.
Citation Format: Wei Hu, Nicholas Arpaia, Jesse A. Green, Ronald C. Hendrickson, Alexander Y. Rudensky. Glucose metabolism and O-linked GlcNAcylation in the tissue repair function of Treg cells [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A072.
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