© 2015 Nature America, Inc. Foxp3+regulatory T cells (Tregcells) are required for immunological homeostasis. One notable distinction between conventional T cells (T conv cells) and Tregcells is differences in the activity of phosphatidylinositol-3-OH kinase (PI(3)K); only T conv cells downregulate PTEN, the main negative regulator of PI(3)K, upon activation. Here we found that control of PI(3)K in Tregcells was essential for lineage homeostasis and stability. Mice lacking Pten in Tregcells developed an autoimmune-lymphoproliferative disease characterized by excessive T helper type 1 (TH1) responses and B cell activation. Diminished control of PI(3)K activity in Tregcells led to reduced expression of the interleukin-2 (IL-2) receptor α subunit CD25, accumulation of Foxp3+CD2+cells and, ultimately, loss of expression of the transcription factor Foxp3 in these cells. Collectively, our data demonstrate that control of PI(3)K signaling by PTEN in Tregcells is critical for maintaining their homeostasis, function and stability.