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

J Exp Med. 2010 Nov 22;207(12):2675-87. doi: 10.1084/jem.20091573. Epub 2010 Nov 8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / physiology
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Dendritic Cells / physiology*
  • Interferon Inducers / pharmacology*
  • Interferon Regulatory Factor-3 / physiology*
  • Interferon-gamma / biosynthesis
  • Interleukin-15 / biosynthesis
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation*
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Poly I-C / pharmacology*


  • Adaptor Proteins, Vesicular Transport
  • INAM protein, mouse
  • Interferon Inducers
  • Interferon Regulatory Factor-3
  • Interleukin-15
  • Irf3 protein, mouse
  • Membrane Glycoproteins
  • TICAM-1 protein, mouse
  • Interferon-gamma
  • Poly I-C