Mechanisms of regulatory T cell lineage homeostasis and stability

Abstract

Defined by the transcription factor Foxp3, regulatory T cells (Tregs) are a lineage of CD4+ T lymphocytes critical for the maintenance of immune homeostasis and tolerance. A lack of functional Tregs in both mice and humans leads to a fatal systemic autoimmune disease, underscoring their importance as mediators of tolerance to self antigen. One notable distinction between conventional T cells (Tconv) and Tregs is their differential control of the phosphatidylinositol 3-kinase (PI3K) pathway: PTEN, the primary negative regulator of PI3K, is expressed at high levels constitutively in Tregs, preventing the downstream activation of PI3K targets. Regulation of signaling through PI3K has previously been described to play an important role in the maintenance of homeostasis in Tconv, but has not been well characterized in Tregs.

Here, we show that control of PI3K in Tregs is essential for the maintenance of in vivo lineage homeostasis and stability. Mice lacking expression of Pten specifically in Foxp3+ Tregs developed an autoimmune/lymphoproliferative disease characterized by excessive TH1 responses, B cell activation and renal failure. Diminished control of PI3K activity in Tregs led to reduced expression of the high-affinity interleukin-2 (IL-2) receptor subunit CD25 and accumulation of Foxp3+CD25- cells in vivo. The downregulation of CD25 expression on PTEN- deficient Tregs preceded the eventual loss of Foxp3 expression in these cells, representing the total destabilization of the Treg lineage and accumulation of “exFoxp3 cells” in vivo. Collectively, these data demonstrate that control of PI3K signaling by PTEN is critical to maintain in vivo Treg homeostasis, function and stability.