Glycogen synthase kinase-3 is essential for Treg development and function

Tregs are critical regulators of the immune response, but the cellular signalling pathways that control their development and homeostasis remain to be determined. We found that glycogen synthase kinase-3 (GSK3), a kinase which integrates signals from AKT and mTOR, was essential for Treg development, restraining fatal autoimmunity. Loss of Gsk3 led to metabolic rewiring in Tregs, with disordered nucleotide metabolism and activation of OxPhos. Acute deletion of Gsk3 did not affect Treg frequency or numbers, but induced an effector gene expression program, and led to the formation of populations with pro-inflammatory signatures. The loss of Gsk3 in Tregs profoundly enhanced anti-tumoral immune responses and suppressed tumour growth.