Article: article from journal or magazin.
Defective TCR signaling events in glycosylphosphatidylinositol-deficient T cells derived from paroxysmal nocturnal hemoglobinuria patients.
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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.
CD4-Positive T-Lymphocytes/drug effects, CD4-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/drug effects, CD8-Positive T-Lymphocytes/immunology, Calcium/metabolism, Dose-Response Relationship, Immunologic, Enzyme Activation, Glycosylphosphatidylinositols/physiology, Hemoglobinuria, Paroxysmal/immunology, Humans, Lymphocyte Activation/drug effects, Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism, Phosphorylation, Protein-Tyrosine Kinases/metabolism, Receptors, Antigen, T-Cell/physiology, Receptors, Antigen, T-Cell, gamma-delta/metabolism, Signal Transduction
Web of science
Last modification date