title: SAP mediates specific cytotoxic T-cell functions in X-linked lymphoproliferative disease.
abstract: Cytotoxic T cells (CTLs) and natural killer cells play a major role in the immune response to Epstein-Barr virus (EBV) infection. In X-linked lymphoproliferative (XLP) disease, a severe immunodeficiency, immunodysregulatory phenomena are observed following EBV infection, suggesting that defects exist in these effector populations. The gene defective in XLP is SAP (signaling lymphocytic activation molecule [SLAM]-associated protein), an adaptor protein that mediates signals through SLAM and other immunoglobulin superfamily receptors including 2B4. We generated EBV-specific T-cell lines from controls and XLP patients and examined CTL function in response to different stimuli. We show that XLP patients can generate EBV-T-cell lines that are phenotypically similar to those from controls. XLP patient EBV-T-cell lines showed a significant decrease in interferon-gamma (IFN-gamma) production in response to 2B4 and autologous EBV-transformed lymphoblastoid cell line (LCL) stimulation but not in response to SLAM. Furthermore, XLP EBV-T-cell lines demonstrated markedly decreased cytotoxic activity against autologous LCLs. By retroviral gene transfer of the SAP gene into XLP EBV-T-cell lines, we show reconstitution of IFN-gamma production and of cytotoxic activity confirming SAP-dependent defects. These studies demonstrate that in XLP the lack of SAP affects specific signaling pathways resulting in severe disruption of CTL function.
authors.affiliation: Molecular Immunology Unit, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Reza
authors.initials: R
authors.lastname: Sharifi
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Sinclair
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: Christine
authors.initials: C
authors.lastname: Kinnon
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
mesh_terms: D015703:Antigens, CD; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D006023:Glycoproteins / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000276:immunology*; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: D015703:Antigens, CD; D002352:Carrier Proteins; D006023:Glycoproteins; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D007371:Interferon-gamma