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Defective TCR signaling events in glycosylphosphatidylinositol-deficient T cells derived from paroxysmal nocturnal hemoglobinuria patients

Romagnoli, Paola ; Bron, Claude

In: International Immunology, 1999, vol. 11, no. 9, p. 1411-1422

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    Title
    • Defective TCR signaling events in glycosylphosphatidylinositol-deficient T cells derived from paroxysmal nocturnal hemoglobinuria patients
    Author
    • Romagnoli, Paola. Institute of Biochemistry, BIL Biomedical Research Centre, University of Lausanne, 1066 Epalinges, Switzerland
    • Bron, Claude. Institute of Biochemistry, BIL Biomedical Research Centre, University of Lausanne, 1066 Epalinges, Switzerland
    Document Type
    • Postprint
    Language
    • English
    Published in
    • International Immunology, 1999, vol. 11, no. 9, p. 1411-1422. Oxford University Press
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:295455
    Summary
    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-CD3ϵ mAb, mutant cells displayed a significantly decreased activation of protein tyrosine kinase p56lck. 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 p56lck contributes to the depressed immune responses observed in GPI-deficient T cells derived from PNH patients