SLAM-associated Protein Deficiency Causes Imbalanced Early Signal Transduction and Blocks Downstream Activation in T Cells from X-linked Lymphoproliferative Disease Patients
| Autor: | Gerhard Fritsch, Maddalena Soncini, Ornella Parolini, Walter Knapp, Thomas M. Stulnig, Wolfgang Holter, Marcus D. Säemann, Maximilian Zeyda, Silvia Sanzone, Fabio Candotti |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Cytoplasm
Time Factors CD3 Complex T-Lymphocytes Biochemistry Antigens CD3 Calcium Carrier Proteins Cell Adhesion Cell Division Cell Line Transformed Flow Cytometry Humans I-kappa B Proteins Interleukin-2 Ionomycin Lymphoproliferative Disorders MAP Kinase Signaling System Mutagens Mutation Phospholipase C gamma Phosphorylation Receptors Antigen T-Cell Receptors Interleukin-2 Retroviridae Tetradecanoylphorbol Acetate Type C Phospholipases Chromosomes Human X Intracellular Signaling Peptides and Proteins Signal Transduction NF-KappaB Inhibitor alpha Receptors Settore BIO/13 - BIOLOGIA APPLICATA Signaling Lymphocytic Activation Molecule Associated Protein IL-2 receptor Cell aggregation medicine.anatomical_structure Antigen Signal transduction Human T cell Biology Chromosomes Cell Line Immune system medicine Antigens Protein kinase A Molecular Biology T-cell receptor X-linked lymphoproliferative disease Cell Biology T-Cell medicine.disease CD3 Transformed Cancer research |
| Zdroj: | Journal of Biological Chemistry. 278:29593-29599 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m300565200 |
| Popis: | Deficiency of SAP (SLAM (signaling lymphocyte activation molecule)-associated protein) protein is associated with a severe immunodeficiency, the X-linked lymphoproliferative disease (XLP) characterized by an inappropriate immune reaction against Epstein-Barr virus infection often resulting in a fatal clinical course. Several studies demonstrated altered NK and T cell function in XLP patients; however, the mechanisms underlying XLP disease are still largely unknown. Here, we show that non-transformed T cell lines obtained from XLP patients were defective in several activation events such as IL-2 production, CD25 expression, and homotypic cell aggregation when cells were stimulated via T cell antigen receptor (TCR).CD3 but not when early TCR-dependent events were bypassed by stimulation with phorbol 12-myristate 13-acetate/ionomycin. Analysis of proximal T cell signaling revealed imbalanced TCR.CD3-induced signaling in SAP-deficient T cells. Although phospholipase C gamma 1 phosphorylation and calcium response were both enhanced in T cells from XLP patients, phosphorylation of VAV and downstream signal transduction events such as mitogen-activated protein kinase phosphorylation and IL-2 production were diminished. Importantly, reconstitution of SAP expression by retroviral-mediated gene transfer completely restored abnormal signaling events in T cell lines derived from XLP patients. In conclusion, SAP mutation or deletion in XLP patients causes profound defects in T cell activation, resulting in immune deficiency. Moreover, these data provide evidence that SAP functions as an essential integrator in early TCR signal transduction. |
| Databáze: | OpenAIRE |
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