The phosphatidylinositol phosphatase PTEN is under control of costimulation and regulates proliferation in human T cells

Schmidt-Weber CB, Wohlfahrt JG, Akdis CA and Blaser K
Source: Eur J Immunol
Publication Date: (2002)
Issue: 32: 1196-1204
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
The authors studied the role of PTEN (phosphatidylinositol phosphatase) activity on PI3K (Phoshatidylinositol 3-kinase) in resting human T cells. PTEN acts as a negative regulator for the PI3-kinase/Akt signaling pathway, which controls and coordinates two major cellular processes: cell cycle progression and cell death. To study PTEN in T cells the authors analyzed whether changes of PTEN affect proliferation in human T cells. PTEN expression was inhibited by nucleofection of PTEN antisense oligonucleotides. Cells were stimulated and proliferation was determined via incorporation of [3H]Thymidine. Samples nucleofected with PTEN antisense oligonucleotide showed increase proliferatin indicating a role of PTEN in cell cycle control.
The phosphatidylinositol phosphatase gene PTEN is a dual specific phosphatase acting on phospho amino acids but also on three phosphorylated inositol phospholipids. Present results demonstrate that PTEN is inducible by costimulatory signals in human CD4(+) T cells. PTEN expression was up-regulated on RNA and protein level in freshly isolated human CD4(+) T cells following stimulation with CD28 or CD2. In contrast, PTEN expression was high but remained CD28 and CD2 unresponsive in lymphoma cells. Intracellular staining revealed PTEN expression in CD4(+) T cell populations stimulated with anti-CD28 or anti-CD28 / anti-CD3. Stimulation with anti-CD3 alone did not induce PTEN expression. Inhibition of PTEN expression by antisense oligonucleotides in CD4(+) T cells stimulated with non-mitogenic anti-CD28 resulted in massively increased proliferation, which was sensitive to the phosphatidylinositol 3-kinase (PI3 K) inhibitor wortmannin. Although CD28 and CD2 induce PI3 K signal transduction, wortmannin did not block PTEN up-regulation by CD28 or CD2 indicating that PTEN gene expression is PI3 K independent. These results demonstrate that PTEN negatively controls costimulatory signals by antagonizing PI3 K activity in the absence of TCR engagement.