Identification of a polyI:C-inducible membrane protein that participates in dendritic cell-mediated natural killer cell activation.
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.
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan.
Takashi
T
Ebihara
Masahiro
M
Azuma
Hiroyuki
H
Oshiumi
Jun
J
Kasamatsu
Kazuya
K
Iwabuchi
Kenji
K
Matsumoto
Hirohisa
H
Saito
Tadatsugu
T
Taniguchi
Misako
M
Matsumoto
Tsukasa
T
Seya
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000502:physiology*; D007369:Interferon Inducers / Q000494:pharmacology*; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011070:Poly I-C / Q000494:pharmacology*
D033942:Adaptor Proteins, Vesicular Transport; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; D007371:Interferon-gamma; D019409:Interleukin-15; D008562:Membrane Glycoproteins; D011070:Poly I-C; C000595458:INAM protein, mouse; C494233:Irf3 protein, mouse; C476286:Ticam1 protein, mouse