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CUTTING EDGE |
*
Centenary Institute for Cancer Medicine and Cell Biology, and University of Sydney, New South Wales, Australia;
Department of Immunology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304;
Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, CA 94143; and
§
Pediatric Oncology, Children’s Hospital of Philadelpiha, Philadelphia, PA 19104
X-linked lymphoproliferative syndrome (XLP) is an immunodeficiency characterized by life-threatening infectious mononucleosis and EBV-induced B cell lymphoma. The gene mutated in XLP encodes SLAM (signaling lymphocytic activation molecule-associated protein)-associated protein (SAP), a small SH2 domain-containing protein. SAP associates with 2B4 and SLAM, activating receptors expressed by NK and T cells, and prevents recruitment of SH2 domain-containing protein tyrosine phosphatase-2 SHP-2) to the cytoplasmic domains of these receptors. The phenotype of XLP may therefore result from perturbed signaling through SAP-associating receptors. We have addressed the functional consequence of SAP deficiency on 2B4-mediated NK cell activation. Ligating 2B4 on normal human NK cells with anti-2B4 mAb or interaction with transfectants bearing the 2B4 ligand CD48 induced NK cell cytotoxicity. In contrast, ligation of 2B4 on NK cells from a SAP-deficient XLP patient failed to initiate cytotoxicity. Despite this, CD2 or CD16-induced cytotoxicity of SAP-deficient NK cells was similar to that of normal NK cells. Thus, selective impairment of 2B4-mediated NK cell activation may contribute to the immunopathology of XLP.
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C. Bloch-Queyrat, M.-C. Fondaneche, R. Chen, L. Yin, F. Relouzat, A. Veillette, A. Fischer, and S. Latour Regulation of natural cytotoxicity by the adaptor SAP and the Src-related kinase Fyn J. Exp. Med., July 5, 2005; 202(1): 181 - 192. [Abstract] [Full Text] [PDF]
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P. Eissmann, L. Beauchamp, J. Wooters, J. C. Tilton, E. O. Long, and C. Watzl Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244) Blood, June 15, 2005; 105(12): 4722 - 4729. [Abstract] [Full Text] [PDF]
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P. Roda-Navarro, M. Mittelbrunn, M. Ortega, D. Howie, C. Terhorst, F. Sanchez-Madrid, and E. Fernandez-Ruiz Dynamic Redistribution of the Activating 2B4/SAP Complex at the Cytotoxic NK Cell Immune Synapse J. Immunol., September 15, 2004; 173(6): 3640 - 3646. [Abstract] [Full Text] [PDF]
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J. M. Mooney, J. Klem, C. Wulfing, L. A. Mijares, P. L. Schwartzberg, M. Bennett, and J. D. Schatzle The Murine NK Receptor 2B4 (CD244) Exhibits Inhibitory Function Independent of Signaling Lymphocytic Activation Molecule-Associated Protein Expression J. Immunol., September 15, 2004; 173(6): 3953 - 3961. [Abstract] [Full Text] [PDF]
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T. Chtanova, S. G. Tangye, R. Newton, N. Frank, M. R. Hodge, M. S. Rolph, and C. R. Mackay T Follicular Helper Cells Express a Distinctive Transcriptional Profile, Reflecting Their Role as Non-Th1/Th2 Effector Cells That Provide Help for B Cells J. Immunol., July 1, 2004; 173(1): 68 - 78. [Abstract] [Full Text] [PDF]
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R. Sharifi, J. C. Sinclair, K. C. Gilmour, P. D. Arkwright, C. Kinnon, A. J. Thrasher, and H. B. Gaspar SAP mediates specific cytotoxic T-cell functions in X-linked lymphoproliferative disease Blood, May 15, 2004; 103(10): 3821 - 3827. [Abstract] [Full Text] [PDF]
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A. Veillette SLAM Family Receptors Regulate Immunity with and without SAP-related Adaptors J. Exp. Med., May 3, 2004; 199(9): 1175 - 1178. [Abstract] [Full Text] [PDF]
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K.-M. Lee, M. E. McNerney, S. E. Stepp, P. A. Mathew, J. D. Schatzle, M. Bennett, and V. Kumar 2B4 Acts As a Non-Major Histocompatibility Complex Binding Inhibitory Receptor on Mouse Natural Killer Cells J. Exp. Med., May 3, 2004; 199(9): 1245 - 1254. [Abstract] [Full Text] [PDF]
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M. Simarro, A. Lanyi, D. Howie, F. Poy, J. Bruggeman, M. Choi, J. Sumegi, M. J. Eck, and C. Terhorst SAP increases FynT kinase activity and is required for phosphorylation of SLAM and Ly9 Int. Immunol., May 1, 2004; 16(5): 727 - 736. [Abstract] [Full Text] [PDF]
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S. G. Tangye, K. E. Nichols, N. J. Hare, and B. C. M. van de Weerdt Functional Requirements for Interactions Between CD84 and Src Homology 2 Domain-Containing Proteins and Their Contribution to Human T Cell Activation J. Immunol., September 1, 2003; 171(5): 2485 - 2495. [Abstract] [Full Text] [PDF]
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C. Li, C. Iosef, C. Y. H. Jia, V. K. M. Han, and S. S.-C. Li Dual Functional Roles for the X-linked Lymphoproliferative Syndrome Gene Product SAP/SH2D1A in Signaling through the Signaling Lymphocyte Activation Molecule (SLAM) Family of Immune Receptors J. Biol. Chem., January 31, 2003; 278(6): 3852 - 3859. [Abstract] [Full Text] [PDF]
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C. Watzl and E. O. Long Natural Killer Cell Inhibitory Receptors Block Actin Cytoskeleton-dependent Recruitment of 2B4 (CD244) to Lipid Rafts J. Exp. Med., January 6, 2003; 197(1): 77 - 85. [Abstract] [Full Text] [PDF]
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J. Klem, P. C. Verrett, V. Kumar, and J. D. Schatzle 2B4 Is Constitutively Associated with Linker for the Activation of T Cells in Glycolipid-Enriched Microdomains: Properties Required for 2B4 Lytic Function J. Immunol., July 1, 2002; 169(1): 55 - 62. [Abstract] [Full Text] [PDF]
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A. Aoukaty and R. Tan Association of the X-linked Lymphoproliferative Disease Gene Product SAP/SH2D1A with 2B4, a Natural Killer Cell-activating Molecule, Is Dependent on Phosphoinositide 3-Kinase J. Biol. Chem., April 5, 2002; 277(15): 13331 - 13337. [Abstract] [Full Text] [PDF]
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S. S. Chuang, P. R. Kumaresan, and P. A. Mathew 2B4 (CD244)-Mediated Activation of Cytotoxicity and IFN-{gamma} Release in Human NK Cells Involves Distinct Pathways J. Immunol., December 1, 2001; 167(11): 6210 - 6216. [Abstract] [Full Text] [PDF]
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A. Bouchon, M. Cella, H. L. Grierson, J. I. Cohen, and M. Colonna Cutting Edge: Activation of NK Cell-Mediated Cytotoxicity by a SAP-Independent Receptor of the CD2 Family J. Immunol., November 15, 2001; 167(10): 5517 - 5521. [Abstract] [Full Text] [PDF]
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M. Martin, X. Romero, M. A. de la Fuente, V. Tovar, N. Zapater, E. Esplugues, P. Pizcueta, J. Bosch, and P. Engel CD84 Functions as a Homophilic Adhesion Molecule and Enhances IFN-{gamma} Secretion: Adhesion Is Mediated by Ig-Like Domain 1 J. Immunol., October 1, 2001; 167(7): 3668 - 3676. [Abstract] [Full Text] [PDF]
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M. Morra, O. Silander, S. Calpe, M. Choi, H. Oettgen, L. Myers, A. Etzioni, R. Buckley, and C. Terhorst Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome Blood, September 1, 2001; 98(5): 1321 - 1325. [Abstract] [Full Text] [PDF]
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R. Sumazaki, H. Kanegane, M. Osaki, T. Fukushima, M. Tsuchida, H. Matsukura, K. Shinozaki, H. Kimura, A. Matsui, and T. Miyawaki SH2D1A mutations in Japanese males with severe Epstein-Barr virus-associated illnesses Blood, August 15, 2001; 98(4): 1268 - 1270. [Abstract] [Full Text] [PDF]
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C. Bottino, M. Falco, S. Parolini, E. Marcenaro, R. Augugliaro, S. Sivori, E. Landi, R. Biassoni, L. D. Notarangelo, L. Moretta, et al. Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus-Infected B Cells in X-Linked Lymphoproliferative Disease J. Exp. Med., August 6, 2001; 194(3): 235 - 246. [Abstract] [Full Text] [PDF]
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J. Sayos, M. Martin, A. Chen, M. Simarro, D. Howie, M. Morra, P. Engel, and C. Terhorst Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP Blood, June 15, 2001; 97(12): 3867 - 3874. [Abstract] [Full Text] [PDF]
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S. S. Chuang, H.-T. K. Pham, P. R. Kumaresan, and P. A. Mathew A Prominent Role for Activator Protein-1 in the Transcription of the Human 2B4 (CD244) Gene in NK Cells J. Immunol., May 15, 2001; 166(10): 6188 - 6195. [Abstract] [Full Text] [PDF]
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L. M. Shlapatska, S. V. Mikhalap, A. G. Berdova, O. M. Zelensky, T. J. Yun, K. E. Nichols, E. A. Clark, and S. P. Sidorenko CD150 Association with Either the SH2-Containing Inositol Phosphatase or the SH2-Containing Protein Tyrosine Phosphatase Is Regulated by the Adaptor Protein SH2D1A J. Immunol., May 1, 2001; 166(9): 5480 - 5487. [Abstract] [Full Text] [PDF]
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M. Takei, T. Ishiwata, K. Mitamura, S. Fujiwara, K. Sasaki, T. Nishi, T. Kuga, T. Ookubo, T. Horie, J. Ryu, et al. Decreased expression of signaling lymphocytic-activation molecule-associated protein (SAP) transcripts in T cells from patients with rheumatoid arthritis Int. Immunol., April 1, 2001; 13(4): 559 - 565. [Abstract] [Full Text] [PDF]
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T. Ulyanova, D. D. Shah, and M. L. Thomas Molecular Cloning of MIS, a Myeloid Inhibitory Siglec, That Binds Protein-tyrosine Phosphatases SHP-1 and SHP-2 J. Biol. Chem., April 20, 2001; 276(17): 14451 - 14458. [Abstract] [Full Text] [PDF]
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M. Morra, M. Simarro-Grande, M. Martin, A. S.-I. Chen, A. Lanyi, O. Silander, S. Calpe, J. Davis, T. Pawson, M. J. Eck, et al. Characterization of SH2D1A Missense Mutations Identified in X-linked Lymphoproliferative Disease Patients J. Biol. Chem., September 21, 2001; 276(39): 36809 - 36816. [Abstract] [Full Text] [PDF]
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 M. J. Czar, E. N. Kersh, L. A. Mijares, G. Lanier, J. Lewis, G. Yap, A. Chen, A. Sher, C. S. Duckett, R. Ahmed, et al. Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP PNAS, June 19, 2001; 98(13): 7449 - 7454. [Abstract] [Full Text] [PDF]
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