Nakamura, HiroyukiZarycki, JodiSullivan, John L.Jung, Jae U.2022-08-232022-08-232001-09-012012-05-01J Immunol. 2001 Sep 1;167(5):2657-65.0022-1767 (Linking)11509608https://hdl.handle.net/20.500.14038/43436The 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.en-USAntigens, CD3Base SequenceCarrier ProteinsCell Transformation, ViralCells, CulturedCytokinesDNA PrimersHerpesvirus 2, SaimiriineHerpesvirus 4, HumanHumans*Intracellular Signaling Peptides and ProteinsLymphoproliferative DisordersMitogen-Activated Protein KinasesMutationOncogene Protein v-cblPhosphorylationProtein-Tyrosine KinasesReceptors, Antigen, T-CellRetroviridae Proteins, OncogenicSignal TransductionT-Lymphocytes, Helper-InducerTyrosineZAP-70 Protein-Tyrosine KinaseImmunology and Infectious DiseasePediatricsJournal Articlehttps://escholarship.umassmed.edu/peds_immunology/202814350peds_immunology/20