Abstract
DAP12, an immunoreceptor tyrosine-based activation motif-bearing adapter protein, is involved in innate immunity mediated by natural killer cells and myeloid cells. We show that DAP12-deficient mouse B cells and B cells from a patient with Nasu-Hakola disease, a recessive genetic disorder resulting from loss of DAP12, showed enhanced proliferation after stimulation with anti-IgM or CpG. Myeloid-associated immunoglobulin-like receptor (MAIR) II (Cd300d) is a DAP12-associated immune receptor. Like DAP12-deficient B cells, MAIR-II-deficient B cells were hyperresponsive. Expression of a chimeric receptor composed of the MAIR-II extracellular domain directly coupled to DAP12 into the DAP12-deficient or MAIR-II-deficient B cells suppressed B cell receptor (BCR)-mediated proliferation. The chimeric MAIR-II-DAP12 receptor recruited the SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1) after BCR stimulation. DAP12-deficient mice showed elevated serum antibodies against self-antigens and enhanced humoral immune responses against T cell-dependent and T cell-independent antigens. Thus, DAP12-coupled MAIR-II negatively regulates B cell-mediated adaptive immune responses.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptive Immunity / immunology*
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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B-Lymphocytes / immunology*
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Electrophoresis, Polyacrylamide Gel
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Flow Cytometry
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Genetic Vectors
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Humans
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Lentivirus
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Lipodystrophy / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Osteochondrodysplasias / immunology*
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
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Receptors, Natural Killer Cell / deficiency
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Receptors, Natural Killer Cell / immunology*
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Receptors, Polymeric Immunoglobulin / deficiency
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Receptors, Polymeric Immunoglobulin / genetics
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Receptors, Polymeric Immunoglobulin / immunology
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Receptors, Polymeric Immunoglobulin / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology*
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Recombinant Fusion Proteins / metabolism
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Subacute Sclerosing Panencephalitis / immunology*
Substances
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Adaptor Proteins, Signal Transducing
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Receptors, Natural Killer Cell
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Receptors, Polymeric Immunoglobulin
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Recombinant Fusion Proteins
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Tyrobp protein, mouse
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myeloid-associated Ig-like receptor , mouse
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Ptpn6 protein, mouse
Supplementary concepts
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Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy