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The immunoreceptor adapter protein DAP12 suppresses B lymphocyte-driven adaptive immune responses.

  • Author(s): Nakano-Yokomizo, Takako;
  • Tahara-Hanaoka, Satoko;
  • Nakahashi-Oda, Chigusa;
  • Nabekura, Tsukasa;
  • Tchao, Nadia K;
  • Kadosaki, Momoko;
  • Totsuka, Naoya;
  • Kurita, Naoki;
  • Nakamagoe, Kiyotaka;
  • Tamaoka, Akira;
  • Takai, Toshiyuki;
  • Yasui, Teruhito;
  • Kikutani, Hitoshi;
  • Honda, Shin-ichiro;
  • Shibuya, Kazuko;
  • Lanier, Lewis L;
  • Shibuya, Akira
  • et al.
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.

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