Cutting Edge: The Phosphoinositide 3-Kinase p110delta Is Critical for the Function of CD4+CD25+Foxp3+ Regulatory T Cells

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) contribute to the maintenance of peripheral tolerance by inhibiting the expansion and function of conventional T cells. Treg development and homeostasis are regulated by the Ag receptor, costimulatory receptors such as CD28 and CTLA-4, and cytokines such as IL-2, IL-10, and TGF-beta. Here we show that the proportions of Tregs in the spleen and lymph nodes of mice with inactive p110 delta PI3K (p110 delta(D910A/D910A)) are reduced despite enhanced Treg selection in the thymus. p110 delta(D910A/D910A) CD4(+)CD25(+) Foxp3(+) Tregs showed attenuated suppressor function in vitro and failed to secrete IL-10. In adoptive transfer experiments, p110 delta(D910A/D910A) T cells failed. to protect against experimental colitis. The identification of p110 delta as an intracellular signaling protein that regulates the activity of CD4(+) CD25(+)Foxp3(+) Tregs may facilitate the further elucidation of the molecular mechanisms responsible for Treg-mediated suppression.