The immunoreceptor adapter protein DAP12 suppresses B lymphocyte-driven adaptive immune responses.
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.
Pubmed ID: 21727189 RIS Download
Adaptive Immunity | Adaptor Proteins, Signal Transducing | Animals | B-Lymphocytes | Electrophoresis, Polyacrylamide Gel | Flow Cytometry | Genetic Vectors | Humans | Lentivirus | Lipodystrophy | Mice | Mice, Inbred C57BL | Mice, Knockout | Osteochondrodysplasias | Protein Tyrosine Phosphatase, Non-Receptor Type 6 | Receptors, Natural Killer Cell | Receptors, Polymeric Immunoglobulin | Recombinant Fusion Proteins | Subacute Sclerosing Panencephalitis