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The dual-function CD150 receptor subfamily: the viral attraction

Nature Immunologyvolume 4pages1924 (2003) | Download Citation



The CD150 subfamily within the CD2 family is a growing group of dual-function receptors that have within their cytoplasmic tails a characteristic signaling motif. The ITSM (immunoreceptor tyrosine-based switch motif) enables these receptors to bind to and be regulated by small SH2 domain adaptor proteins, including SH2D1A (SH2-containing adaptor protein SH2 domain protein 1A) and EAT-2 (EWS-activated transcript 2). A major signaling pathway through the prototypic receptor in this subfamily, CD150, leads to the activation of interferon-γ, a key cytokine for viral immunity. As a result, many viruses have designed strategies to usurp or alter CD150 functions. Measles virus uses CD150 as a receptor and Molluscum contagiosum virus encodes proteins that are homologous to CD150. Thus, viruses use CD150 subfamily receptors to create a favorable environment to elude detection and destruction. Understanding the CD150 subfamily may lead to new strategies for vaccine development and antiviral therapies.

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  1. 1

    Sharpe, A.H. & Freeman, G.J. The B7-CD28 superfamily. Nat. Rev. Immunol. 2, 116–126 (2002).

  2. 2

    Veillette, A., Latour, S. & Davidson, D. Negative regulation of immunoreceptor signaling. Annu. Rev. Immunol. 20, 669–707 (2002).

  3. 3

    Coffey, A.J. et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat. Genet. 20, 129–135 (1998).

  4. 4

    Nichols, K.E. et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc. Natl. Acad. Sci. USA 95, 13765–13770 (1998).

  5. 5

    Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998).

  6. 6

    Brandau, O. et al. Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP). Hum. Mol. Genet. 8, 2407–2413 (1999).

  7. 7

    Strahm, B. et al. Recurrent B-cell non-Hodgkin's lymphoma in two brothers with X-linked lymphoproliferative disease without evidence for Epstein-Barr virus infection. Br. J. Haematol. 108, 377–382 (2000).

  8. 8

    Arico, M. et al. Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Blood 97, 1131–1133 (2001).

  9. 9

    Morra, M. et al. Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome. Blood 98, 1321–1325 (2001).

  10. 10

    Sidorenko, S.P. & Clark, E.A. Characterization of a cell surface glycoprotein IPO-3, expressed on activated human B and T lymphocytes. J. Immunol. 151, 4614–4624 (1993).

  11. 11

    Cocks, B.G. et al. A novel receptor involved in T-cell activation. Nature 376, 260–263 (1995).

  12. 12

    Tangye, S.G., Phillips, J.H. & Lanier, L.L. The CD2-subset of the Ig superfamily of cell surface molecules: receptor-ligand pairs expressed by NK cells and other immune cells. Semin. Immunol. 12, 149–157 (2000).

  13. 13

    Bottino, C. et al. NTB-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. 194, 235–246 (2001).

  14. 14

    Boles, K.S., Stepp, S.E., Bennett, M., Kumar, V. & Mathew, P.A. 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunol. Rev. 181, 234–249 (2001).

  15. 15

    Bouchon, A., Cella, M., Grierson, H.L., Cohen, J.I. & Colonna, M. Activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family. J. Immunol. 167, 5517–5521 (2001).

  16. 16

    Kingsbury, G.A. et al. Cloning, expression, and function of BLAME, a novel member of the CD2 family. J. Immunol. 166, 5675–5680 (2001).

  17. 17

    Fennelly, J.A., Tiwari, B., Davis, S.J. & Evans, E.J. CD2F-10: a new member of the CD2 subset of the immunoglobulin superfamily. Immunogenetics 53, 599–602 (2001).

  18. 18

    Fraser, C.C. et al. Identification and characterization of SF2000 and SF2001, two new members of the immune receptor SLAM/CD2 family. Immunogenetics 53, 843–850 (2002).

  19. 19

    Morra, M. et al. X-linked lymphoproliferative disease: a progressive immunodeficiency. Annu Rev. Immunol. 19, 657–682 (2001).

  20. 20

    Wang, N. et al. CD150 is a member of a family of genes that encode glycoproteins on the surface of hematopoietic cells. Immunogenetics 53, 382–394 (2001).

  21. 21

    Tangye, S.G., Phillips, J.H., Lanier, L.L. & Nichols, K.E. Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. J. Immunol. 165, 2932–2936 (2000).

  22. 22

    Polacino, P.S., Pinchuk, L.M., Sidorenko, S.P. & Clark, E.A. Immunodeficiency virus cDNA synthesis in resting T lymphocytes is regulated by T cell activation signals and dendritic cells. J. Med. Primatol. 25, 201–209 (1996).

  23. 23

    Kruse, M. et al. Signaling lymphocytic activation molecule is expressed on mature CD83+ dendritic cells and is up-regulated by IL-1 β. J. Immunol. 167, 1989–1995 (2001).

  24. 24

    Punnonen, J. et al. Soluble and membrane-bound forms of signaling lymphocytic activation molecule (SLAM) induce proliferation and Ig synthesis by activated human B lympohocytes. J. Exp. Med. 185, 993–1004 (1997).

  25. 25

    Mavaddat, N. et al. Signaling lymphocytic activation molecule (CDw150) is homophilic but self-associates with very low affinity. J. Biol. Chem. 275, 28100–28109 (2000).

  26. 26

    Chuang, S.S., Kumaresan, P.R. & Mathew, P.A. 2B4 (CD244)-mediated activation of cytotoxicity and IFN-γ release in human NK cells involves distinct pathways. J. Immunol. 167, 6210–6216 (2001).

  27. 27

    Sivori, S. et al. Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation. Proc. Natl. Acad. Sci. USA 99, 4526–4531 (2002).

  28. 28

    Henning, G. et al. Signaling lymphocytic activation molecule (SLAM) regulates T cellular cytotoxicity. Eur. J. Immunol. 31, 2741–2750 (2001).

  29. 29

    Castro, A.G. et al. Molecular and functional characterization of mouse signaling lymphocytic activation molecule (SLAM): differential expression and responsiveness in Th1 and Th2 cells. J. Immunol. 163, 5860–5870 (1999).

  30. 30

    Aversa, G. et al. SLAM and its role in T cell activation and Th cell responses. Immunol. Cell. Biol. 75, 202–205 (1997).

  31. 31

    Mikhalap, S.V. et al. CDw150 associates with src-homology 2-containing inositol phosphatase and modulates CD95-mediated apoptosis. J. Immunol. 162, 5719–5727 (1999).

  32. 32

    Shlapatska, L.M. et al. CD150 modulates CD95-mediated apoptosis. in Leucocyte Typing VII (eds. Mason, D. et al.) 60–63 (Oxford University Press, Oxford, 2002).

  33. 33

    Tangye, S.G., van de Weerdt, B.C., Avery, D.T. & Hodgkin, P.D. CD84 is up-regulated on a major population of human memory B cells and recruits the SH2 domain containing proteins SAP and EAT-2. Eur. J. Immunol. 32, 1640–1649 (2002).

  34. 34

    Latour, S. & Veillette, A. Proximal protein tyrosine kinases in immunoreceptor signaling. Curr. Opin. Immunol. 13, 299–306 (2001).

  35. 35

    Latour, S. et al. Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nat. Immunol. 2, 681–690 (2001).

  36. 36

    Howie, D. et al. Molecular dissection of the signaling and costimulatory functions of CD150 (SLAM): CD150/SAP binding and CD150-mediated costimulation. Blood 99, 957–965 (2002).

  37. 37

    Tangye, S.G. et al. Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. J. Immunol. 162, 6981–6985 (1999).

  38. 38

    Sayos, J. et al. Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP. Blood 97, 3867–3874 (2001).

  39. 39

    Aoukaty, A. & Tan, R. Association of the XLP gene product SAP/SH2D1A with 2B4, a natural killer cell activating molecule, is dependent on phosphoinositide 3-kinase. J. Biol. Chem. 277, 13331–13337 (2002).

  40. 40

    Shlapatska, L.M. et al. 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. 166, 5480–5487 (2001).

  41. 41

    Tatsuo, H., Ono, N., Tanaka, K. & Yanagi, Y. SLAM (CDw150) is a cellular receptor for measles virus. Nature 406, 893–897 (2000).

  42. 42

    Nedellec, P. et al. Bgp2, a new member of the carcinoembryonic antigen-related gene family, encodes an alternative receptor for mouse hepatitis viruses. J. Virol. 68, 4525–4537 (1994).

  43. 43

    Okazaki, T., Maeda, A., Nishimura, H., Kurosaki, T. & Honjo, T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc. Natl. Acad. Sci. USA 98, 13866–13871 (2001).

  44. 44

    Kitzig, F., Martinez-Barriocanal, A., Lopez-Botet, M. & Sayos, J. Cloning of two new splice variants of Siglec-10 and mapping of the interaction between Siglec-10 and SHP-1. Biochem. Biophys. Res. Commun. 296, 355–362 (2002).

  45. 45

    Gold, M.R. et al. Targets of B-cell antigen receptor signaling: the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway and the Rap1 GTPase. Immunol. Rev. 176, 47–68 (2000).

  46. 46

    Gu, H. et al. New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway. Mol. Cell. Biol. 20, 7109–7120 (2000).

  47. 47

    Phee, H., Jacob, A. & Coggeshall, K.M. Enzymatic activity of the Src homology 2 domain-containing inositol phosphatase is regulated by a plasma membrane location. J. Biol. Chem. 275, 19090–19097 (2000).

  48. 48

    Harmer, S.L. & DeFranco, A.L. The src homology domain 2-containing inositol phosphatase SHIP forms a ternary complex with Shc and Grb2 in antigen receptor-stimulated B lymphocytes. J. Biol. Chem. 274, 12183–12191 (1999).

  49. 49

    Sylla, B.S. et al. The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-κB. Proc. Natl. Acad. Sci. USA 97, 7470–7475 (2000).

  50. 50

    Li, S.C. et al. Novel mode of ligand binding by the SH2 domain of the human XLP disease gene product SAP/SH2D1A. Curr. Biol. 9, 1355–1362 (1999).

  51. 51

    Morra, M. et al. Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. EMBO J. 20, 5840–5852 (2001).

  52. 52

    Nagy, N. et al. SH2D1A and SLAM protein expression in human lymphocytes and derived cell lines. Int. J. Cancer 88, 439–447 (2000).

  53. 53

    Poy, F. et al. Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition. Mol. Cell 4, 555–561 (1999).

  54. 54

    Tortorella, D., Gewurz, B.E., Furman, M.H., Schust, D.J. & Ploegh, H.L. Viral subversion of immune system. Annu. Rev. Immunol. 18, 861–926 (2000).

  55. 55

    Klein, G. & Klein, E. Sinking surveillance's flagship. Nature 395, 441–444 (1998).

  56. 56

    Bugert, J.J. & Darai, G. Poxvirus homologues of cellular genes. Virus Genes 21, 111–133 (2000).

  57. 57

    Tatsuo, H., Ono, N. & Yanagi, Y. Morbilliviruses use signaling lymphocyte activation molecules (CD150) as cellular receptors. J. Virol. 75, 5842–5850 (2001).

  58. 58

    Koike, S., Ise, I. & Nomoto, A. Functional domains of the poliovirus receptor. Proc. Natl. Acad. Sci. USA 88, 4104–4108 (1991).

  59. 59

    Kirkitadze, M.D. & Barlow, P.N. Structure and flexibility of the multiple domain proteins that regulate complement activation. Immunol. Rev. 180, 146–161 (2001).

  60. 60

    Mori, Y. et al. Human herpesvirus 6 variant A but not variant B induces fusion from without in a variety of human cells through a human herpesvirus entry receptor, CD46. J. Virol. 76, 6760–6761 (2002).

  61. 61

    Ono, N. et al. Measles viruses on throat swabs from measles patients use signaling lymphocytic activation molecule (CDw150) but not CD46 as a cellular receptor. J. Virol. 75, 4399–4401 (2001).

  62. 62

    Hsu, E.C., Iorio, C., Sarangi, F., Khine, A.A. & Richardson, C.D. CDw150 (SLAM) is a receptor for a lymphotropic strain of measles virus and may account for the immunosuppressive properties of this virus. Virology 279, 9–21 (2001).

  63. 63

    Erlenhofer, C., Duprex, W.P., Rima, B.K., ter Meulen, V. & Schneider-Schaulies, J. Analysis of receptor (CD46, CD150) usage by measles virus. J. Genet. Virol. 83, 1431–1436 (2002).

  64. 64

    Minagawa, H., Tanaka, K., Ono, N., Tatsuo, H. & Yanagi, Y. Induction of the measles virus receptor SLAM (CD150) on monocytes. J. Genet. Virol. 82, 2913–2917 (2001).

  65. 65

    Schneider, U., von Messling, V., Devaux, P. & Cattaneo, R. Efficiency of measles virus entry and dissemination through different receptors. J. Virol. 76, 7460–7467 (2002).

  66. 66

    Ono, N., Tatsuo, H., Tanaka, K., Minagawa, H. & Yanagi, Y. V domain of human SLAM (CDw150) is essential for its function as a measles virus receptor. J. Virol. 75, 1594–1600 (2001).

  67. 67

    Schneider-Schaulies, S., Niewiesk, S., Schneider-Schaulies, J. & ter Meulen, V. Measles virus induced immunosuppression: targets and effector mechanisms. Curr. Mol. Med. 1, 163–181 (2001).

  68. 68

    Erlenhoefer, C. et al. CD150 (SLAM) is a receptor for measles virus but is not involved in viral contact-mediated proliferation inhibition. J. Virol. 75, 4499–4505 (2001).

  69. 69

    Tanaka, K., Minagawa, H., Xie, M.F. & Yanagi, Y. The measles virus hemagglutinin downregulates the cellular receptor SLAM (CD150). Arch. Virol. 147, 195–203 (2002).

  70. 70

    Fugier-Vivier, I. et al. Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells. J. Exp. Med. 186, 813–823 (1997).

  71. 71

    Servet-Delprat, C. et al. Measles virus induces abnormal differentiation of CD40 ligand-activated human dendritic cells. J. Immunol. 164, 1753–1760 (2000).

  72. 72

    Schneider-Schaulies, S., Bieback, K., Avota, E., Klagge, I. & ter Meulen, V. Regulation of gene expression in lymphocytes and antigen-presenting cells by measles virus: consequences for immunomodulation. J. Mol. Med. 80, 73–85 (2002).

  73. 73

    Bolt, G., Berg, K. & Blixenkrone-Moller, M. Measles virua-induced modulation of host-cell gene expression. J. Genet. Virol. 83, 1157–1165 (2002).

  74. 74

    Meroni, L. et al. Altered signaling lymphocytic activation molecule (SLAM) expression in HIV infection and redirection of HIV-specific responses via SLAM triggering. Clin. Immunol. 92, 276–284 (1999).

  75. 75

    Senkevich, T.G., Koonin, E.V., Bugert, J.J., Darai, G. & Moss, B. The genome of molluscum contagiosum virus: analysis and comparison with other poxviruses. Virology 233, 19–42 (1997).

  76. 76

    Senkevich, T.G. et al. Genome sequence of a human tumorigenic poxvirus: prediction of specific host response-evasion genes. Science 273, 813–816 (1996).

  77. 77

    Bugert, J.J., Melquiot, N.V. & Darai, G. Mapping of mRNA transcripts in the genome of molluscum contagiosum virus: transcriptional analysis of the viral slam gene family. Virus Genes 21, 189–192 (2000).

  78. 78

    Sumegi, J. et al. Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood 96, 3118–3125 (2000).

  79. 79

    Sidorenko, S.P. et al. Monoclonal antibodies of IPO series against B cell differentiation antigens in leukemia and lymphoma immunophenotyping. Neoplasma 39, 3–9 (1992).

  80. 80

    Nakajima, H. & Colonna, M. 2B4: an NK cell activating receptor with unique specificity and signal transduction mechanism. Hum. Immunol. 61, 39–43 (2000).

  81. 81

    Parolini, S. et al. X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus–infected cells. J. Exp. Med. 192, 337–346 (2000).

  82. 82

    Tangye, S.G., Cherwinski, H., Lanier, L.L. & Phillips, J.H. 2B4-mediated activation of human natural killer cells. Mol. Immunol. 37, 493–501 (2000).

  83. 83

    Howie, D., Sayos, J., Terhorst, C. & Morra, M. The gene defective in X-linked lymphoproliferative disease controls T cell dependent immune surveillance against Epstein-Barr virus. Curr. Opin. Immunol. 12, 474–478 (2000).

  84. 84

    Nakamura, H., Zarycki, J., Sullivan, J.L. & Jung, J.U. Abnormal T cell receptor signal transduction of CD4 Th cells in X-linked lymphoproliferative syndrome. J. Immunol. 167, 2657–2665 (2001).

  85. 85

    Nelson, D.L. & Terhorst, C. X-linked lymphoproliferative syndrome. Clin. Exp. Immunol. 122, 291–295 (2000).

  86. 86

    Czar, M.J. et al. Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. Proc. Natl. Acad. Sci. USA 98, 7449–7454 (2001).

  87. 87

    Wu, C. et al. SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nat. Immunol. 2, 410–414 (2001).

  88. 88

    Benoit, L., Wang, X., Pabst, H.F., Dutz, J. & Tan, R. Defective NK cell activation in X-linked lymphoproliferative disease. J. Immunol. 165, 3549–3553 (2000).

  89. 89

    Sadelain, M. & Kieff, E. Why commonplace encounters turn to fatal attraction. Nat. Genet. 20, 103–104 (1998).

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We thank members of biotechnology group of IEPOR and other colleagues for helpful discussions and H. Floyd and E. Floyd for helpful comments. Supported by INTAS grant 011-2382 (to S.P.S.), U.S. Civilian Research and Development Foundation grant UB2-531 (to S.P.S.) and National Institutes of Health Grant GM37905 (to E.A.C).

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  1. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology NAS Ukraine, 45 Vasylkivska str., Kiev, 03022, Ukraine

    • Svetlana P. Sidorenko
  2. Departments of Microbiology and Immunology, University of Washington, Box 357242, Seattle, 98195, 1959 NE, Pacific, WA, USA

    • Edward A. Clark


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