Cutting Edge: The Phosphoinositide 3-Kinase p110δ Is Critical for the Function of CD4+CD25+Foxp3+ Regulatory T Cells

Abstract

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-β. Here we show that the proportions of Tregs in the spleen and lymph nodes of mice with inactive p110δ PI3K (p110δD910A/D910A) are reduced despite enhanced Treg selection in the thymus. p110δD910A/D910A CD4+CD25+Foxp3+ Tregs showed attenuated suppressor function in vitro and failed to secrete IL-10. In adoptive transfer experiments, p110δD910A/D910A T cells failed to protect against experimental colitis. The identification of p110δ 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.

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

“…The Idd9 interval also includes other genes of interest such as p110d and mTOR, known to be involved in Treg differentiation and function (50)(51)(52), as well as several zinc finger proteins containing Kr€ uppel-associated box domains, which can be involved in cell differentiation and development. Therefore, careful dissection of the Idd9 region is essential to pinpoint the genes of interest.…”

T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR

“…Evidence for an involvement of the PI3K/Akt/mTOR network in Treg differentiation and function has been accumulating: Treg cell numbers increase in the thymi of PI3K p110␦-deficient mice (37), rapamycin can promote Treg cell differentiation in specific settings (18)(19)(20), and exciting data published while this manuscript was under review indicate that Akt signaling interferes with Foxp3 expression in vitro and in vivo (38). Our data provide a rationale for these genetic and pharmacological data by demonstrating that (i) TCR signaling controls Foxp3 expression via a signaling network with the key components PI3K␣ and ␦, Akt, and mTOR, the mammalian target of rapamycin, and (ii) the timing of PI3K/Akt/ mTOR inhibition relative to TCR signaling is critical for the outcome.…”

“…The ability of small molecule inhibitors to block PI3K/mTOR/Akt signaling temporarily rather than permanently may be beneficial because constitutive p110␦ deficiency promotes the differentiation of Treg cells in the thymus, but impairs their subsequent maintenance in the periphery (26,37).…”

Efficacy of cisplatin-based immunochemotherapy plus alloSCT in high-risk chronic lymphocytic leukemia: final results of a prospective multicenter phase 2 HOVON study

“…The pros and cons of continuing BCRi post alloSCT are also unknown as there are concerns for a possible higher incidence of GvHD under either idelalisib or ibrutinib because of inhibition of regulatory T-cell function 48 and increased Th1 T-cell activity, 49 respectively.…”