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International Immunology, Vol. 11, No. 9, 1411-1422, September 1999
© 1999 Japanese Society for Immunology

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

Paola Romagnoli and Claude Bron

Institute of Biochemistry, BIL Biomedical Research Centre, University of Lausanne, 1066 Epalinges, Switzerland

Correspondence to: P. Romagnoli, U395 INSERM, BP 3028, 31024 Toulouse Cedex 3, France

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-CD3{epsilon} 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.

Keywords: glycosylphosphatidylinositol, paroxysmal nocturnal hemoglobinuria, TCR signaling

Transmitting editor: L. Moretta


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