title: SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells.
abstract: The adaptor protein SAP regulates signaling through signaling lymphocytic activation molecule (SLAM)-family receptors expressed on T and natural killer (NK) cells. In patients affected by X-linked lymphoproliferative (XLP) disease, mutations in the SH2D1A gene result in defective lytic activity. However, the mechanism by which SAP controls cytotoxic activity remains unclear. T-cell-receptor (TCR) activation of CD8(+) cytotoxic T cells (CTLs) results in down-regulation of SAP, suggesting that this protein is involved in early activation events. Here, we show that SAP-deficient CTLs from patients with XLP and hemophagocytic lymphohistiocytosis (HLH) display a specific lytic defect against autologous and allogeneic Epstein-Barr virus (EBV)-positive B cells. This defect is associated with the defective polarization of 2B4, perforin, and lipid rafts at the contact area of CTLs with EBV-positive targets. Blockade of 2B4 in normal CTLs reproduces the defects in lysis and polarization observed in SAP-deficient CTLs. Expression and regulation of the SLAM-family receptors SLAM, CD84, and 2B4, as well as the lytic effectors perforin and granzyme-B are normal in SAP-deficient CTLs. In addition, TCR stimulation leads to normal proliferation and production of interleukin 2 (IL-2), IL-4, and interferon-gamma (IFN-gamma). These results demonstrate that the SAP/2B4 pathway plays a key role in CTL lytic activity against EBV-positive targets by promoting the polarization of the lytic machinery.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, via Olgettina 58, 20132 Milan, Italy.
authors.forename: Loïc
authors.initials: L
authors.lastname: Dupré
authors.forename: Grazia
authors.initials: G
authors.lastname: Andolfi
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Rita
authors.initials: R
authors.lastname: Clementi
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Aricò
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Roncarolo
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D003602:Cytotoxicity, Immunologic; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000473:pathology; D053804:Granzymes; D015616:Histiocytosis, Non-Langerhans-Cell / Q000235:genetics / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family
chemical_list: D015703:Antigens, CD; C084093:CD244 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases