Identification of a polyI:C-inducible membrane protein that participates in dendritic cell-mediated natural killer cell activation

Takashi Ebihara, Masahiro Azuma, Hiroyuki Oshiumi, Jun Kasamatsu, Kazuya Iwabuchi, Kenji Matsumoto, Hirohisa Saito, Tadatsugu Taniguchi, Misako Matsumoto, Tsukasa Seya

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68 Citations (Scopus)

Abstract

In myeloid dendritic cells (mDCs), TLR3 is expressed in the endosomal membrane and interacts with the adaptor toll/interleukin 1 receptor homology domain-containing adaptor molecule 1 (TICAM-1; TRIF). TICAM-1 signals culminate in interferon (IFN) regulatory factor (IRF) 3 activation. Co-culture of mDC pretreated with the TLR3 ligand polyI:C and natural killer (NK) cells resulted in NK cell activation. This activation was triggered by cell-to-cell contact but not cytokines. Using expression profiling and gain/loss-of-function analyses of mDC genes, we tried to identify a TICAM-1-inducing membrane protein that participates in mDC-mediated NK activation. Of the nine candidates screened, one contained a tetraspanin-like sequence and satisfied the screening criteria. The protein, referred to as IRF-3-dependent NK-activating molecule (INAM), functioned in both the mDC and NK cell to facilitate NK activation. In the mDC, TICAM-1, IFN promoter stimulator 1, and IRF-3, but not IRF-7, were required for mDC-mediated NK activation. INAM was minimally expressed on NK cells, was up-regulated in response to polyI:C, and contributed to mDC-NK reciprocal activation via its cytoplasmic tail, which was crucial for the activation signal in NK cells. Adoptive transfer of INAM-expressing mDCs into mice implanted with NK-sensitive tumors caused NK-mediated tumor regression. We identify a new pathway for mDC-NK contact-mediated NK activation that is governed by a TLR signal-derived membrane molecule.

Original languageEnglish
Pages (from-to)2675-2687
Number of pages13
JournalJournal of Experimental Medicine
Volume207
Issue number12
DOIs
Publication statusPublished - 2010 Nov 22

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Ebihara, T., Azuma, M., Oshiumi, H., Kasamatsu, J., Iwabuchi, K., Matsumoto, K., Saito, H., Taniguchi, T., Matsumoto, M., & Seya, T. (2010). Identification of a polyI:C-inducible membrane protein that participates in dendritic cell-mediated natural killer cell activation. Journal of Experimental Medicine, 207(12), 2675-2687. https://doi.org/10.1084/jem.20091573