Abnormal T cell receptor signal transduction of CD4 Th cells in X-linked lymphoproliferative syndrome

UMMS Affiliation

Department of Pediatrics; Program in Molecular Medicine

Publication Date


Document Type



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


Immunology and Infectious Disease | Pediatrics


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.


J Immunol. 2001 Sep 1;167(5):2657-65.

Journal/Book/Conference Title

Journal of immunology (Baltimore, Md. : 1950)

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