NK-activating dendritic cells are elicited by stimulation with Toll-like receptor 3

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Double-stranded （ds）RNA-recognition receptors reside in the cytoplasm and membranes of cells. Thesereceptors are implicated in the differential screening of microbes by the host. Myeloid dendritic cells （mDCs）recognize and respond to polyI:C, an analog of dsRNA, by endosomal TLR3 and cytoplasmic MDA5. NK cells areinduced in vivo by the administration of polyI:C to mice and in vitro are reciprocally activated by mDCs, although themolecular mechanisms as yet undetermined. Here, we show that the TLR adapter TICAM-1 （TRIF） participates inmDC-derived antitumor NK activation. In a syngeneic mouse tumor implant model, intraperitoneal administration ofpolyI:C led to the retardation of tumor growth, which eff ect relied largely on NK activation. This NK-dependent tumorregression did not occur in TICAM-1-/- or IFNAR-/- mice, while 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 lackof TICAM-1 did not aff ect IFN production but resulted in unresponsiveness to IL-12 production, mDC maturation andpolyI:C-mediated antitumor activity. This NK activation required NK-mDC contact in in vitro transwell analysis. NKantitumoractivity was successfully introduced into tumor-implanted mice by transferring mDCs expressing TICAM-1.Implanted tumor growth in IFNAR-/- mice was retarded by adoptively transferring polyI:C-treated TICACM-1-positivemDCs but not TICAM-1-/- mDCs. Thus, TICAM-1 rather than MDA5 in mDCs critically facilitated mDC-NK contactand activation of antitumor NK, resulting in the regression of low MHC-expressing tumors
弘前大学の論文

NK-activating dendritic cells are elicited by stimulation with Toll-like receptor 3

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