Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability

Foxp3(+) regulatory T cells (T-reg cells) are required for immunological homeostasis. One notable distinction between conventional T cells (T-conv cells) and T-reg cells 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 T-reg cells was essential for lineage homeostasis and stability. Mice lacking Pten in T-reg cells developed an autoimmune-lymphoproliferative disease characterized by excessive T helper type 1 (T(H)1) responses and B cell activation. Diminished control of PI(3)K activity in T-reg cells led to reduced expression of the interleukin-2 (IL-2) receptor alpha subunit CD25, accumulation of Foxp3(+) CD25(-) 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 T-reg cells is critical for maintaining their homeostasis, function and stability.