We have previously identified a subset of common variable immunodeficiency (CVID) patients with defective T cell function associated with impaired activation of the TCR-dependent tyrosine phosphorylation cascade. Here we have assessed the structural and functional integrity of the principal components involved in coupling the TCR/CD3 complex to intracellular tyrosine kinases in two of these patients. We show that ZAP-70 fails to bind the signaling-competent CD3zeta tyrosine phosphorylation isoform and to become activated following TCR engagement, suggesting that defective recruitment of ZAP-70 might underlie the TCR signaling dysfunction in these patients. Determination of the nucleotide sequences encoding the intracellular domains of the CD3/zeta subunits and ZAP-70 did not reveal any mutation. Furthermore, ZAP-70 from these patients could interact in vitro with recombinant phospho-zeta, ruling out genetic defects at the immunoreceptor tyrosine-based activation motif/SH2 domain interface responsible for ZAP-70 recruitment to the activated TCR. No defect was found in expression, activity or subcellular localization of Lck, which is thought to be primarily responsible for CD3zeta phosphorylation. Hence, while the T cell defect in these CVID patients can be pinpointed to the interaction between ZAP-70 and CD3zeta, the integrity in the components of the signaling machinery involved in this process suggests that additional components might be required for completion of this step.

Boncristiano, M., Majolini, M.B., D'Elios, M.M., Pacini, S., Valensin, S., Ulivieri, C., et al. (2000). Defective recruitment and activation of ZAP-70 in CVID patients with T-cell defects. EUROPEAN JOURNAL OF IMMUNOLOGY, 30(9), 2632-2638.

Defective recruitment and activation of ZAP-70 in CVID patients with T-cell defects.

D'ELIOS M. M.;ULIVIERI, CRISTINA;BALDARI, COSIMA
2000-01-01

Abstract

We have previously identified a subset of common variable immunodeficiency (CVID) patients with defective T cell function associated with impaired activation of the TCR-dependent tyrosine phosphorylation cascade. Here we have assessed the structural and functional integrity of the principal components involved in coupling the TCR/CD3 complex to intracellular tyrosine kinases in two of these patients. We show that ZAP-70 fails to bind the signaling-competent CD3zeta tyrosine phosphorylation isoform and to become activated following TCR engagement, suggesting that defective recruitment of ZAP-70 might underlie the TCR signaling dysfunction in these patients. Determination of the nucleotide sequences encoding the intracellular domains of the CD3/zeta subunits and ZAP-70 did not reveal any mutation. Furthermore, ZAP-70 from these patients could interact in vitro with recombinant phospho-zeta, ruling out genetic defects at the immunoreceptor tyrosine-based activation motif/SH2 domain interface responsible for ZAP-70 recruitment to the activated TCR. No defect was found in expression, activity or subcellular localization of Lck, which is thought to be primarily responsible for CD3zeta phosphorylation. Hence, while the T cell defect in these CVID patients can be pinpointed to the interaction between ZAP-70 and CD3zeta, the integrity in the components of the signaling machinery involved in this process suggests that additional components might be required for completion of this step.
Boncristiano, M., Majolini, M.B., D'Elios, M.M., Pacini, S., Valensin, S., Ulivieri, C., et al. (2000). Defective recruitment and activation of ZAP-70 in CVID patients with T-cell defects. EUROPEAN JOURNAL OF IMMUNOLOGY, 30(9), 2632-2638.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/21900
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