Antitumor NK activation induced by the Toll-like receptor 3-TICAM-1 (TRIF) pathway in myeloid dendritic cells
Antitumor NK activation induced by the Toll-like receptor 3-TICAM-1 (TRIF) pathway in myeloid dendritic cells
复制标题
DOI：
10.1073/pnas.0605978104
复制
发表时间：
2007-01-02
影响因子：
11.1
通讯作者：
Seya, Tsukasa
中科院分区：
文献类型：
--
作者：
Akazawa, Takashi;Ebihara, Takashi;Seya, Tsukasa
髓样树突状细胞（mDC）通过内体Toll样受体（TLR）3和胞质受体识别并应答dsRNA的类似物polyl：C。自然杀伤（NK）细胞在体内通过向小鼠施用polyI：C而被激活，并且在体外通过mDC而被间接激活，尽管分子机制尚未确定。在这里，我们表明，TLR接头TICAM-1（TRIF）参与mDC衍生的抗肿瘤INK激活。在同基因小鼠肿瘤植入模型（C57 BL/6与具有低H-2表达者的B16黑素瘤）中，腹腔内给予polyl：C导致肿瘤生长的阻滞，这是依赖于INK活化的作用。这种NK依赖性肿瘤消退在TICAM-1（-/-）或IFNAR（-/-）小鼠中未发生，而在PKR-/-、MyD 88（-/-）、IFN-β（-/-）和野生型小鼠中诱导了正常的NK抗肿瘤应答。IFNAR是诱导IFN-α/β和TLR 3的先决条件。TICAM-1的缺乏不影响IFN的产生，但导致对IL-12产生、mDC成熟和多聚I：C介导的NK抗肿瘤活性的无反应性。在体外transwell分析中，这种NK活化需要NK-mDC接触，但不需要IL-12功能。IFNAR（-/-）小鼠中的植入肿瘤生长通过过继性转移polyI：C处理的TICACM-1阳性mDC而不是TICAM-1（-/-）mDC而被延迟。因此，mDC中的TICAM-1关键地促进mDC-NK接触和抗肿瘤INK的活化，导致低MHC表达肿瘤的消退。
Myeloid dendritic cells (mDCs) recognize and respond to polyl: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 polyl:C to mice and in vitro 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 INK activation. In a syngeneic mouse tumor implant model (C57BL/6 vs. B16 melanoma with low H-2 expresser), i.p. administration of polyl:C led to the retardation of tumor growth, an effect relied on by INK 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 polyl:C-mediated NK-antitumor activity. This NK activation required NK-mDC contact but not IL-12 function in in vitro transwell analysis. Implanted tumor growth in IFNAR(-/-) mice was retarded by adoptively transferring polyl: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 INK, resulting in the regression of low MHC-expressing tumors.