Abnormal T cell receptor signal transduction of CD4 Th cells in X-linked lymphoproliferative syndrome.
The molecular basis of X-linked lymphoproliferative (XLP) disease has been attributed to mutations in the signaling lymphocytic activation molecule-associated protein (SAP), an src homology 2 domain-containing intracellular signaling molecule known to interact with the lymphocyte-activating surface receptors signaling lymphocytic activation molecule and 2B4. To investigate the effect of SAP defects ... on TCR signal transduction, herpesvirus saimiri-immortalized CD4 Th cells from XLP patients and normal healthy individuals were examined for their response to TCR stimulation. CD4 T cells of XLP patients displayed elevated levels of tyrosine phosphorylation compared with CD4 T cells from healthy individuals. In addition, downstream serine/threonine kinases are constitutively active in CD4 T cells of XLP patients. In contrast, TCR-mediated activation of Akt, c-Jun-NH(2)-terminal kinases, and extracellular signal-regulated kinases in XLP CD4 T cells was transient and rapidly diminished when compared with that in control CD4 T cells. Consequently, XLP CD4 T cells exhibited severe defects in up-regulation of IL-2 and IFN-gamma cytokine production upon TCR stimulation and in MLRs. Finally, SAP specifically interacted with a 75-kDa tyrosine-phosphorylated protein upon TCR stimulation. These results demonstrate that CD4 T cells from XLP patients exhibit aberrant TCR signal transduction and that the defect in SAP function is likely responsible for this phenotype.
Mesh Terms:
Antigens, CD3, Base Sequence, Carrier Proteins, Cell Transformation, Viral, Cells, Cultured, Cytokines, DNA Primers, Herpesvirus 2, Saimiriine, Herpesvirus 4, Human, Humans, Intracellular Signaling Peptides and Proteins, Lymphoproliferative Disorders, Mitogen-Activated Protein Kinases, Mutation, Oncogene Protein v-cbl, Phosphorylation, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, Retroviridae Proteins, Oncogenic, Signal Transduction, T-Lymphocytes, Helper-Inducer, Tyrosine, ZAP-70 Protein-Tyrosine Kinase
Antigens, CD3, Base Sequence, Carrier Proteins, Cell Transformation, Viral, Cells, Cultured, Cytokines, DNA Primers, Herpesvirus 2, Saimiriine, Herpesvirus 4, Human, Humans, Intracellular Signaling Peptides and Proteins, Lymphoproliferative Disorders, Mitogen-Activated Protein Kinases, Mutation, Oncogene Protein v-cbl, Phosphorylation, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, Retroviridae Proteins, Oncogenic, Signal Transduction, T-Lymphocytes, Helper-Inducer, Tyrosine, ZAP-70 Protein-Tyrosine Kinase
J. Immunol.
Date: Sep. 01, 2001
PubMed ID: 11509608
View in: Pubmed Google Scholar
Download Curated Data For This Publication
142083
Switch View:
- Interactions 1