Antitumor NK activation induced by the Toll-like receptor 3-TICAM-1 (TRIF) pathway in myeloid dendritic cells.
Myeloid dendritic cells (mDCs) recognize and respond to polyI:C, an analog of dsRNA, by endosomal Toll-like receptor (TLR) 3 and cytoplasmic receptors. Natural killer (NK) cells are activated in vivo by the administration of polyI:C to mice and in vivo are reciprocally activated by mDCs, although the molecular mechanisms are as yet undetermined. Here, we show that the TLR adaptor TICAM-1 (TRIF) participates in mDC-derived antitumor NK activation. In a syngeneic mouse tumor implant model (C57BL/6 vs. B16 melanoma with low H-2 expresser), i.p. administration of polyI:C led to the retardation of tumor growth, an effect relied on by NK activation. This NK-dependent tumor regression did not occur in TICAM-1(-/-) or IFNAR(-/-) mice, whereas a normal NK antitumor response was induced in PKR(-/-), MyD88(-/-), IFN-beta(-/-), and wild-type mice. IFNAR was a prerequisite for the induction of IFN-alpha/beta and TLR3. The lack of TICAM-1 did not affect IFN production but resulted in unresponsiveness to IL-12 production, mDC maturation, and polyI:C-mediated NK-antitumor activity. This NK activation required NK-mDC contact but not IL-12 function in in vivo transwell analysis. Implanted tumor growth in IFNAR(-/-) mice was retarded by adoptively transferring polyI:C-treated TICACM-1-positive mDCs but not TICAM-1(-/-) mDCs. Thus, TICAM-1 in mDCs critically facilitated mDC-NK contact and activation of antitumor NK, resulting in the regression of low MHC-expressing tumors.
Akazawa
Takashi
T
Department of Immunology, Osaka Medical Center for Cancer, Nakamichi 1-3-2, Higashinari-ku, Osaka 537-8511, Japan.
Ebihara
Takashi
T
Okuno
Manabu
M
Okuda
Yu
Y
Shingai
Masashi
M
Tsujimura
Kunio
K
Takahashi
Toshitada
T
Ikawa
Masahito
M
Okabe
Masaru
M
Inoue
Norimitsu
N
Okamoto-Tanaka
Miki
M
Ishizaki
Hiroyoshi
H
Miyoshi
Jun
J
Matsumoto
Misako
M
Seya
Tsukasa
T
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D011070:Poly I-C / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D011070:Poly I-C; D053633:Receptor, Interferon alpha-beta; D051196:Toll-Like Receptor 3; C508032:Ifnar1 protein, mouse; C476286:Ticam1 protein, mouse