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. 2000 Aug 7;192(3):337-46. doi: 10.1084/jem.192.3.337.

Abstract

2B4 is a surface molecule involved in activation of the natural killer (NK) cell-mediated cytotoxicity. It binds a protein termed Src homology 2 domain-containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway. In this study, we analyzed patients with X-linked lymphoproliferative disease (XLP), a severe inherited immunodeficiency characterized by critical mutations in the SH2D1A gene and by the inability to control Epstein-Barr virus (EBV) infections. We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis. Other receptors involved in NK cell triggering, including CD16, NKp46, NKp44, and NKp30, displayed a normal functional capability. However, their activating function was inhibited upon engagement of 2B4 molecules. CD48, the natural ligand of 2B4, is highly expressed on the surface of EBV(+) B cell lines. Remarkably, NK cells from XLP patients could not kill EBV(+) B cell lines. This failure was found to be the consequence of inhibitory signals generated by the interaction between 2B4 and CD48, as the antibody-mediated disruption of the 2B4-CD48 interaction restored lysis of EBV(+) target cells lacking human histocompatibility leukocyte antigen (HLA) class I molecules. In the case of autologous or allogeneic (HLA class I(+)) EBV(+) lymphoblastoid cell lines, restoration of lysis was achieved only by the simultaneous disruption of 2B4-CD48 and NK receptor-HLA class I interactions. Molecular analysis revealed that 2B4 molecules isolated from either XLP or normal NK cells were identical. As expected, in XLP-NK cells, 2B4 did not associate with SH2D1A, whereas similar to 2B4 molecules isolated from normal NK cells, it did associate with Src homology 2 domain-containing phosphatase 1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigens, CD*
  • Base Sequence
  • Carrier Proteins / genetics
  • Cell Line
  • Cell Membrane / metabolism
  • Child, Preschool
  • DNA, Complementary
  • Genetic Linkage
  • Herpesvirus 4, Human / immunology*
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / virology
  • Lymphocyte Activation / immunology
  • Lymphoproliferative Disorders / blood
  • Lymphoproliferative Disorders / genetics
  • Lymphoproliferative Disorders / immunology*
  • Male
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / physiology
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • Natural Cytotoxicity Triggering Receptor 1
  • Receptors, Immunologic / immunology*
  • Receptors, Immunologic / metabolism
  • Signal Transduction*
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family
  • Tumor Cells, Cultured
  • X Chromosome*

Substances

  • Antigens, CD
  • CD244 protein, human
  • Carrier Proteins
  • DNA, Complementary
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NCR1 protein, human
  • Natural Cytotoxicity Triggering Receptor 1
  • Receptors, Immunologic
  • SH2D1A protein, human
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family

Associated data

  • GENBANK/AJ245376
  • GENBANK/AJ245377