Graduate Student University of Pittsburgh, United States
Introduction/Rationale: Regulatory T cells (Tregs) are essential for maintaining self-tolerance and immune homeostasis. In different tissue environments, Tregs differentiate into diverse subtypes, enabling them to acquire specialized properties and regulate a wide range of immune responses. We and others have reported that glucose metabolic conditions define Tregs with distinct phenotypes and functional properties. Glucose transporter 1 (Glut1) is primarily responsible for regulating glucose uptake in Tregs; however, its specific role in controlling Treg function across different tissue environments remains poorly understood.
Methods: Using a specific Glut1-receptor binding domain (Glut1-RBD), we assessed surface Glut1 levels in Tregs from various tissues. To further investigate the role of Glut1 in Tregs across tissues, we employed Slc2a1flox/flox Foxp3GFP-Cre-ERT2 mice to selectively delete Glut1 in Treg cells following tamoxifen administration. We then explored the impact of altered glucose uptake ability on Treg cell phenotypes and functions within different disease models.
Results: We found that surface Glut1 is highly expressed in Tregs from the skin and gut, but relatively low in brain, tumor and other lymphoid organs. In B16-F10 and MC38 tumor models, Glut1 deletion in Tregs accelerated tumor growth, accompanied by increased expression of inhibitory molecules and enhanced suppressive activity within the tumor microenvironment. In the experimental autoimmune encephalomyelitis (EAE) model, Glut1-deficient Tregs conferred enhanced protection against CNS autoimmunity. In striking contrast, mice with Glut1-deficient Tregs exhibited increased susceptibility to imiquimod-induced skin inflammation and DSS-induced colitis, characterized by rapid disease onset, reduced Treg infiltration, and impaired suppressive function.
Conclusion: These differential phenotypes across tumor and inflammatory models suggest that Glut1, play context-dependent roles in modulating Treg responses according to their local metabolic environment.
