Antitumor NK activation induced by the Toll-like receptor 3-TICAM-1 (TRIF) pathway in myeloid dendritic cells
| Autor: | Yu Okuda, Manabu Okuno, Masaru Okabe, Toshitada Takahashi, Hiroyoshi Ishizaki, Jun Miyoshi, Norimitsu Inoue, Takashi Akazawa, Takashi Ebihara, Tsukasa Seya, Misako Matsumoto, Kunio Tsujimura, Miki Okamoto-Tanaka, Masashi Shingai, Masahito Ikawa |
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| Rok vydání: | 2007 |
| Předmět: |
Myeloid
Melanoma Experimental Receptor Interferon alpha-beta Biology Lymphocyte Activation Mice In vivo medicine Animals Myeloid Cells Receptor Mice Inbred BALB C Toll-like receptor Multidisciplinary Melanoma Signal transducing adaptor protein Dendritic Cells Biological Sciences medicine.disease Toll-Like Receptor 3 Cell biology Killer Cells Natural Mice Inbred C57BL Adaptor Proteins Vesicular Transport Poly I-C medicine.anatomical_structure TRIF TLR3 |
| Zdroj: | Proceedings of the National Academy of Sciences. 104:252-257 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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-β −/− , and wild-type mice. IFNAR was a prerequisite for the induction of IFN-α/β 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. |
| Databáze: | OpenAIRE |
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