PIP3 pathway in regulatory T cells and autoimmunity

Abstract

Regulatory T cells (Tregs) play an important role in preventing both autoimmune and inflammatory diseases. Many recent studies have focused on defining the signal transduction pathways essential for the development and the function of Tregs. Increasing evidence suggest that T-cell receptor (TCR), interleukin-2 (IL-2) receptor (IL-2R), and co-stimulatory receptor signaling are important in the early development, peripheral homeostasis, and function of Tregs. The phosphoinositide-3 kinase (PI3K)-regulated pathway (PIP3 pathway) is one of the major signaling pathways activated upon TCR, IL-2R, and CD28 stimulation, leading to T-cell activation, proliferation, and cell survival. Activation of the PIP3 pathway is also negatively regulated by two phosphatidylinositol phosphatases SHIP and PTEN. Several mouse models deficient for the molecules involved in PIP3 pathway suggest that impairment of PIP3 signaling leads to dysregulation of immune responses and, in some cases, autoimmunity. This review will summarize the current understanding of the importance of the PIP3 pathway in T-cell signaling and the possible roles this pathway performs in the development and the function of Tregs.

Phosphatidylinositol-3,4,5-Triphosphate and Cellular Signaling: Implications for Obesity and Diabetes

“…PI3Kδ and PI3Kγ mediated production of PtdIns(3,4,5)P 3 has been found to be an important target in a range of inflammatory and autoimmune diseases as well as in transplantation and hematological malignancies [201, 202]. In response to various extracellular stimuli, different cellular receptors such as antigen, cytokine, or chemokine receptors activate PtdIns(3,4,5)P 3 signaling in the immune system [203]. PtdIns(3,4,5)P 3 then recruits and activates GEF for Rac and Arf GTPases, resulting in actin cytoskeletal rearrangement and directional cellular movement [204].…”

“…It has been suggested that PI3Kγ mediates chemotaxis in T-cells, whereas PI3Kδ is responsible for the migration of B-cells [221]. Several studies reported that both increased and decreased PtdIns(3,4,5)P 3 signaling have been associated with the development of autoimmunity, suggesting that PtdIns(3,4,5)P 3 plays a role in the regulation of the functions of T-cells [203, 222, 223]. The evidence discussed above provides information supporting the importance of PtdIns(3,4,5)P 3 signaling in immune function and diseases.…”

Genetic or pharmaceutical blockade of p110δ phosphoinositide 3-kinase enhances IgE production

“…As such, the development of PI3K isoform-specific inhibitors is currently an area of intense activity. 9,13,14 In vivo inactivation of the class IA isoform p110d has been found to reduce antigen receptor function, T H 2 cytokine production, and T H 2-mediated inflammatory reactions. [15][16][17] These studies suggest that targeting p110d might be effective for the treatment of human allergy or atopic asthma.…”

Analysis of Phosphatidylinositol 3,4,5-Trisphosphates of PTEN Expression on Mammalian Cells

“…9,10 Several studies showed that natural oncogenic form of PI3-Kinases caused elevation in PIP 3 levels, activation of Akt and tumor progression. 8,11,12 Some recent studies showed that PIP 3 s were degraded by the two inositol phosphatases, SHIP (SH2-containing inositol phosphatase, dephosphorylates PIP 3 at the 5 position to produce PI(3,4)-P 2 ) and PTEN (phosphatase and tensine homolog, hydrolyzes PIP 3 at the 3-position to produce PI(4,5-P 2 ).…”