The brain-type glucose transporter GLUT3 controls the function of regulatory T cells

• Applicant: Martin Väth, Ph.D.
• Subject Area: Immunology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448344585

T regulatory (Treg) cells are indispensable to maintain immunological tolerance and organ homeostasis by suppressing detrimental (auto-) immune responses. At the metabolic level, Foxp3-expressing Treg cells differ remarkably from their conventional T cell counterparts as they are less dependent on glycolysis but rely instead on mitochondrial respiration and fatty acid oxidation. This notion is supported by the fact that pharmacological inhibition of glycolysis in vitro and genetic ablation of the glucose transporter GLUT1 in mice selectively inhibits effector T cells but does not perturb the immunoregulatory function of Treg cells. The simplified view that Treg cells operate in a ‘glycolysis-independent’ manner was, however, challenged by recent findings that selected functions of Treg cells in vivo, such as their migration to inflamed tissues, are dependent on glucose and glycolysis. Our preliminary data revealed that Treg cells express high levels of the ‘brain-type’ glucose transporter, GLUT3, but the role of GLUT3 in the immune system and in Treg cells specifically is not known. The premise that GLUT3 is essential for normal Treg function is supported by our findings that mice with Treg-specific deletion of the Slc2a3 gene (encoding for GLUT3) showed a defective Treg homeostasis and developed an early-onset, fatal autoimmune syndrome. How GLUT3 controls the homeostasis and function of Treg cells at the molecular level is, however, not known. In this research project, we will compare WT and GLUT3-deficient Treg cells at the functional (aim 1), metabolic (aim 2), transcriptional (aim 3) and epigenetic level (aim 4) with the ultimate goal to define the function of GLUT3 in lymphoid and tissue-resident Treg cells. The results of this study are not only important to better understand the physiology of Treg cells in general, but will also define novel molecular mechanisms for the treatment of inflammatory diseases and advanced cancer immunotherapy in the future.

• DFG Programme: Research Grants