Phosphatase PP2A is requisite for the function of regulatory T cells

Regulatory T cells use a distinct metabolism to exert their regulatory function. Tsokos and colleagues show that the phosphatase PP2A suppresses the metabolic-checkpoint kinase complex mTORC1 in these cells and is necessary for their function. PP2A activity is regulated by the cellular abundance of ceramide via a transcription factor Foxp3–dependent feedback mechanism. Homeostasis of the immune system depends on the proper function of regulatory T cells (Treg cells). Compromised suppressive activity of Treg cells leads to autoimmune disease and graft rejection and promotes anti-tumor immunity. Here we report a previously unrecognized requirement for the serine-threonine phosphatase PP2A in the function of Treg cells. Treg cells exhibited high PP2A activity, and Treg cell–specific ablation of the PP2A complex resulted in a severe, multi-organ, lymphoproliferative autoimmune disorder. Mass spectrometry revealed that PP2A associated with components of the mTOR metabolic-checkpoint kinase pathway and suppressed the activity of the mTORC1 complex. In the absence of PP2A, Treg cells altered their metabolic and cytokine profile and were unable to suppress effector immune responses. Therefore, PP2A is required for the function of Treg cells and the prevention of autoimmunity.