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

Takako Nakano-Yokomizo, Satoko Tahara-Hanaoka, Chigusa Nakahashi-Oda, Tsukasa Nabekura, Nadia K. Tchao, Momoko Kadosaki, Naoya Totsuka, Naoki Kurita, Kiyotaka Nakamagoe, Akira Tamaoka, Toshiyuki Takai, Teruhito Yasui, Hitoshi Kikutani, Shin Ichiro Honda, Kazuko Shibuya, Lewis L. Lanier, Akira Shibuya

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1661-1671
Number of pages11
JournalJournal of Experimental Medicine
Volume208
Issue number18
DOIs
Publication statusPublished - 2011 Aug 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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