title: Defective TCR signaling events in glycosylphosphatidylinositol-deficient T cells derived from paroxysmal nocturnal hemoglobinuria patients.
abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disorder characterized by the presence of abnormal cells of various hematopoietic cell lineages deficient in surface expression of glycosylphosphatidylinositol (GPI)-anchored molecules. By analyzing T cells isolated from patients affected with PNH, it was found that ex vivo GPI-deficient CD4(+) and CD8(+) peripheral T cells display a more naive phenotype as compared to wild-type cells. In addition, in vitro proliferative responses to allogeneic antigen-presenting cells were shown to be reduced in mutant T cells. To investigate the molecular basis responsible for defective T cell activation in GPI-deficient T cells, T cell lines and T cell clones were generated from patients affected with PNH. When stimulated with anti-CD3epsilon mAb, mutant cells displayed a significantly decreased activation of protein tyrosine kinase p56(lck). The decreased kinase activity was accompanied by a delayed TCR capping and internalization. Interestingly, protein tyrosine phosphorylation is not only quantitatively but also qualitatively affected, with one substrate being more intensively phosphorylated in mutant than in wild-type cells. These observations suggest that a defective activation of p56(lck) contributes to the depressed immune responses observed in GPI-deficient T cells derived from PNH patients.
authors.affiliation: Institute of Biochemistry, BIL Biomedical Research Centre, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Romagnoli
authors.forename: C
authors.initials: C
authors.lastname: Bron
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation; D017261:Glycosylphosphatidylinositols / Q000502:physiology*; D006457:Hemoglobinuria, Paroxysmal / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017261:Glycosylphosphatidylinositols; D011948:Receptors, Antigen, T-Cell; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium