Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antibodies, Monoclonal / pharmacology
-
Antigens, CD*
-
Carrier Proteins / biosynthesis
-
Carrier Proteins / genetics
-
Carrier Proteins / physiology*
-
Cell Line
-
Cytotoxicity Tests, Immunologic
-
Cytotoxicity, Immunologic / genetics
-
Genetic Linkage
-
Glycoproteins / genetics
-
Glycoproteins / physiology*
-
Humans
-
Immunoglobulins / genetics
-
Immunoglobulins / physiology*
-
Immunologic Deficiency Syndromes / genetics
-
Immunologic Deficiency Syndromes / immunology
-
Intracellular Signaling Peptides and Proteins*
-
Killer Cells, Natural / immunology*
-
Leukocytes, Mononuclear / immunology
-
Leukocytes, Mononuclear / metabolism
-
Lymphocyte Activation / genetics
-
Lymphocyte Activation / immunology*
-
Lymphoproliferative Disorders / genetics
-
Lymphoproliferative Disorders / immunology*
-
Membrane Glycoproteins / biosynthesis
-
Membrane Glycoproteins / immunology
-
Membrane Glycoproteins / physiology*
-
Mice
-
Receptors, Cell Surface
-
Receptors, Immunologic / biosynthesis
-
Receptors, Immunologic / physiology*
-
Signaling Lymphocytic Activation Molecule Associated Protein
-
Signaling Lymphocytic Activation Molecule Family
-
Signaling Lymphocytic Activation Molecule Family Member 1
-
Syndrome
-
Tumor Cells, Cultured
-
X Chromosome
-
src Homology Domains / genetics
-
src Homology Domains / immunology
Substances
-
Antibodies, Monoclonal
-
Antigens, CD
-
CD244 protein, human
-
Carrier Proteins
-
Cd244a protein, mouse
-
Glycoproteins
-
Immunoglobulins
-
Intracellular Signaling Peptides and Proteins
-
Membrane Glycoproteins
-
Receptors, Cell Surface
-
Receptors, Immunologic
-
SH2D1A protein, human
-
Sh2d1a protein, mouse
-
Signaling Lymphocytic Activation Molecule Associated Protein
-
Signaling Lymphocytic Activation Molecule Family
-
Signaling Lymphocytic Activation Molecule Family Member 1