Functional analysis of auto-reactive T cell clones in idiopathic thrombacytopenic purpura

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To explore the interaction between dendritic cells/T cells and the platelet membrane protein, GPIIb-IIIa, we established T cell clones recognizing the GPIIb amino acid sequences from patients with idiopathic thrombocytopenic purpura (ITP). These clones were composed of CD4+ helper T cells and CD8+ cytotoxic T cells. The HP patients with CD8+ T cell clones showed lower number of megakaryocytes in bone marrow, as compared with patients with CD4+ helper T cell clones. This finding suggests that CD8+ cytotoxic T cells destruct autologous platelets in some ITP patients. Platelet destruction in ITP has been believed to be mediated by autoantibody. Our results suggest T cell-mediated cytotoxicity is an alternative mechanism for platelet destruction in a subset of ITP and that different autoimmune-mediated mechanisms are involved in pathogenesis of ITP.We also examined structure and function of the GPIIb-IIIa molecule by using an expression system for mutated recombinant GPIIb -Ma on the surface of mammalian cells. We identified amino acids critical for regulation of GPIIb-IIIa activation in a certain loop of extracellular domain of GPIIIa. Moreover, we found two amino acids critical for regulation of GPIIb-IIIa activation in the cytoplasmic domain of GPIIIa and that these two residues cooperatively regulate talin-mediated GPIIb-IIIa activation.