Cross-priming for antitumor CTL induced by soluble Ag + polyI:C depends on the TICAM-1 pathway in mouse CD11c(+)/CD8α(+) dendritic cells.
Cross-priming for antitumor CTL induced by soluble Ag + polyI:C depends on the TICAM-1 pathway in mouse CD11c(+)/CD8α(+) dendritic cells.
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DOI：
10.4161/onci.19893
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发表时间：
2012-08-01
期刊：
影响因子：
7.2
通讯作者：
Seya T
中科院分区：
文献类型：
--
作者：
Azuma M;Ebihara T;Oshiumi H;Matsumoto M;Seya T
PolyI:C 是一种核苷酸模式分子，可诱导骨髓树突状细胞 (DC) 中外源 Ag 的交叉呈递以及细胞毒性 T 淋巴细胞 (CTL) 的 MHC I 类依赖性增殖。 DC（BM 或脾 CD8α+）具有 dsRNA 传感器，包括 PolyI:C，以发出促进交叉呈递的信号。据报道，内体 TLR3 和细胞质 RIG-I/MDA5 负责 PolyI:C 传感，并推测分别通过 TICAM-1 (TRIF) 和 IPS-1 (MAVS、Cardif、VISA) 适配器传递交叉呈递信号。事实上，当肿瘤相关Ag（TAA）与DC中的polyI:C同时摄取时，DC在同基因小鼠模型中交叉引发了针对TAA的CTL。在这里，我们测试了 TICAM-1 或 IPS-1 通路中的哪一个参与了肿瘤相关可溶性 Ag 的交叉呈递，并在同基因肿瘤植入系统 EG7/C57BL6 和外源攻击可溶性 Ag（EG7 裂解物）和 PolyI:C 的环境中延迟肿瘤生长。当EG7裂解物和polyI:C皮下注射到荷瘤小鼠中时，在野生型和较小程度上的IPS-1−/−小鼠中观察到EG7肿瘤生长迟缓，但在TICAM-1−/−小鼠中没有观察到。 IRF-3/7 是必需的，但 IPS-1 和 I 型 IFN 很少参与 PolyI:C 介导的 CTL 增殖。尽管 TICAM-1 和 IPS-1 都有助于 CD8α+ DC 中 CD86/CD40 的上调，但 H2Kb-SL8 四聚体和 OT-1 增殖测定表明，OVA 识别的 CD8 T 细胞主要通过 TICAM-1 和 CD8α+ DC 在体内增殖，这在离体分析中至关重要。最终，多聚 I:C 给药后 8 天以上肿瘤消退。结果推断，如果 TICAM-1 信号同时出现在肿瘤周围的 CD8α+ DC 中，可溶性肿瘤 Ag 会诱导肿瘤生长迟缓，即具有治疗潜力。
PolyI:C is a nucleotide pattern molecule that induces cross-presentation of foreign Ag in myeloid dendritic cells (DC) and MHC Class I-dependent proliferation of cytotoxic T lymphocytes (CTL). DC (BM or spleen CD8α+) have sensors for dsRNA including polyI:C to signal facilitating cross-presentation. Endosomal TLR3 and cytoplasmic RIG-I/MDA5 are reportedly responsible for polyI:C sensing and presumed to deliver signal for cross-presentation via TICAM-1 (TRIF) and IPS-1 (MAVS, Cardif, VISA) adaptors, respectively. In fact, when tumor-associated Ag (TAA) was simultaneously taken up with polyI:C in DC, the DC cross-primed CTL specific to the TAA in a syngenic mouse model. Here we tested which of the TICAM-1 or IPS-1 pathway participate in cross-presentation of tumor-associated soluble Ag and retardation of tumor growth in the setting with a syngeneic tumor implant system, EG7/C57BL6, and exogenously challenged soluble Ag (EG7 lysate) and polyI:C. When EG7 lysate and polyI:C were subcutaneously injected in tumor-bearing mice, EG7 tumor growth retardation was observed in wild-type and to a lesser extent IPS-1−/− mice, but not TICAM-1−/− mice. IRF-3/7 were essential but IPS-1 and type I IFN were minimally involved in the polyI:C-mediated CTL proliferation. Although both TICAM-1 and IPS-1 contributed to CD86/CD40 upregulation in CD8α+ DC, H2Kb-SL8 tetramer and OT-1 proliferation assays indicated that OVA-recognizing CD8 T cells predominantly proliferated in vivo through TICAM-1 and CD8α+ DC is crucial in ex vivo analysis. Ultimately, tumor regresses > 8 d post polyI:C administration. The results infer that soluble tumor Ag induces tumor growth retardation, i.e., therapeutic potential, if the TICAM-1 signal coincidentally occurs in CD8α+ DC around the tumor.
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DOI：
10.1084/jem.20091573
发表时间：
2010-11-22
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ebihara T;Azuma M;Oshiumi H;Kasamatsu J;Iwabuchi K;Matsumoto K;Saito H;Taniguchi T;Matsumoto M;Seya T
通讯作者：
Seya T
影响因子：
4.4
作者：
Asano, Jumpei;Tada, Hiroyuki;Ohteki, Toshiaki
通讯作者：
Ohteki, Toshiaki
影响因子：
4.4
作者：
Kaiser, WJ;Offermann, MK
通讯作者：
Offermann, MK
影响因子：
3.1
作者：
BERRY, LJ;SMYTHE, DS;ACTOR, P
通讯作者：
ACTOR, P
通过体内肽免疫诱导卵蛋白特异性细胞毒性T细胞。
影响因子：
15.3
作者：
CARBONE, FR;BEVAN, MJ
通讯作者：
BEVAN, MJ