title: Abnormal T cell receptor signal transduction of CD4 Th cells in X-linked lymphoproliferative syndrome.
abstract: 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.
authors.affiliation: Department of Microbiology and Molecular Genetics, New England Regional Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: J
authors.initials: J
authors.lastname: Zarycki
authors.forename: J L
authors.initials: JL
authors.lastname: Sullivan
authors.forename: J U
authors.initials: JU
authors.lastname: Jung
mesh_terms: D001483:Base Sequence; D017252:CD3 Complex / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers / Q000235:genetics; D006567:Herpesvirus 2, Saimiriine; D004854:Herpesvirus 4, Human; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D050722:Oncogene Protein v-cbl; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D002352:Carrier Proteins; D016207:Cytokines; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D050722:Oncogene Protein v-cbl; D011948:Receptors, Antigen, T-Cell; D015682:Retroviridae Proteins, Oncogenic; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D020928:Mitogen-Activated Protein Kinases