title: SLAM-associated protein deficiency causes imbalanced early signal transduction and blocks downstream activation in T cells from X-linked lymphoproliferative disease patients.
abstract: Deficiency of SAP (SLAM (signaling lymphocyte activation molecule)-associated protein) protein is associated with a severe immunodeficiency, the X-linked lymphoproliferative disease (XLP) characterized by an inappropriate immune reaction against Epstein-Barr virus infection often resulting in a fatal clinical course. Several studies demonstrated altered NK and T cell function in XLP patients; however, the mechanisms underlying XLP disease are still largely unknown. Here, we show that non-transformed T cell lines obtained from XLP patients were defective in several activation events such as IL-2 production, CD25 expression, and homotypic cell aggregation when cells were stimulated via T cell antigen receptor (TCR).CD3 but not when early TCR-dependent events were bypassed by stimulation with phorbol 12-myristate 13-acetate/ionomycin. Analysis of proximal T cell signaling revealed imbalanced TCR.CD3-induced signaling in SAP-deficient T cells. Although phospholipase C gamma 1 phosphorylation and calcium response were both enhanced in T cells from XLP patients, phosphorylation of VAV and downstream signal transduction events such as mitogen-activated protein kinase phosphorylation and IL-2 production were diminished. Importantly, reconstitution of SAP expression by retroviral-mediated gene transfer completely restored abnormal signaling events in T cell lines derived from XLP patients. In conclusion, SAP mutation or deletion in XLP patients causes profound defects in T cell activation, resulting in immune deficiency. Moreover, these data provide evidence that SAP functions as an essential integrator in early TCR signal transduction.
authors.affiliation: Centro Ricerche Parco Scientifico E. Menni, Ospedale Poliambulanza, Brescia 25124, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sanzone
authors.forename: Maximilian
authors.initials: M
authors.lastname: Zeyda
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Saemann
authors.forename: Maddalena
authors.initials: M
authors.lastname: Soncini
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Holter
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritsch
authors.forename: Walter
authors.initials: W
authors.lastname: Knapp
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Stulnig
authors.forename: Ornella
authors.initials: O
authors.lastname: Parolini
mesh_terms: D017252:CD3 Complex / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002448:Cell Adhesion; D002455:Cell Division; D002461:Cell Line, Transformed; D041321:Chromosomes, Human, X; D003593:Cytoplasm / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D015759:Ionomycin / Q000494:pharmacology; D008232:Lymphoproliferative Disorders / Q000097:blood / Q000235:genetics*; D020935:MAP Kinase Signaling System; D009153:Mutagens; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D002352:Carrier Proteins; D020672:I-kappa B Proteins; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D009153:Mutagens; C000606204:NFKBIA protein, human; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000072000:NF-KappaB Inhibitor alpha; D015759:Ionomycin; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium