title: The phosphatidylinositol phosphatase PTEN is under control of costimulation and regulates proliferation in human T cells.
abstract: 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.
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland. csweber@siaf.unizh.ch
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Schmidt-Weber
authors.forename: Jan G
authors.initials: JG
authors.lastname: Wohlfahrt
authors.forename: Cezmi A
authors.initials: CA
authors.lastname: Akdis
authors.forename: Kurt
authors.initials: K
authors.lastname: Blaser
mesh_terms: D000328:Adult; D000730:Androstadienes / Q000494:pharmacology; D018801:CD2 Antigens / Q000502:physiology*; D018106:CD28 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D002453:Cell Cycle; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology / Q000201:enzymology; D004789:Enzyme Activation; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013873:Thionucleotides / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000201:enzymology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D018801:CD2 Antigens; D018106:CD28 Antigens; D004791:Enzyme Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D013873:Thionucleotides; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin; C494929:PTEN protein, human