Efficient stimulation of T cell responses by human IFN-α-induced dendritic cells does not require toll-like receptor triggering
Efficient stimulation of T cell responses by human IFN-α-induced dendritic cells does not require toll-like receptor triggering
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DOI：
10.1097/cji.0b013e318174a52a
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发表时间：
2008-06-01
影响因子：
3.9
通讯作者：
Spagnoli, Giulio C.
中科院分区：
文献类型：
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作者：
Bracci, Laura;Schumacher, Reto;Spagnoli, Giulio C.
树突状细胞 (DC) 可以被促炎细胞因子或 Toll 样受体 (TLR) 触发而激活。这些刺激诱导表型调节和基因表达谱的特定模式。我们研究了 TLR 触发是否代表在粒细胞巨噬细胞集落刺激因子和干扰素-α (IFN-DC) 存在的情况下，单核细胞培养产生的人 DC 诱导 T 细胞反应的不可或缺的要求。作为模型刺激剂，我们选择咪唑喹诺酮 (3M-001)，这是一种合成的 TLR7 激动剂，用于治疗皮肤感染和肿瘤，并作为实验佐剂。与在粒细胞巨噬细胞集落刺激因子和白细胞介素(IL-4)存在下培养单核细胞产生的DC(IL-4-DC)不同，IFN-DC表现出半成熟表型。此外，在稳定状态下，例如在没有TLR触发的情况下，IFN-DC而非IL-4-DC能够诱导CD4(+)和CD8(+)T细胞应答。 3M-001 处理可诱导 IFN-DC 中共刺激分子表面表达的上调以及 IL-12 和 IL-6 的“从头”产生。然而，TLR7触发未能显着增强IFN-DC诱导抗原特异性细胞毒性T淋巴细胞和刺激同种异体CD4(+) T细胞的能力。这些数据表明，TLR 参与和 IL-12 产生并不代表 IFN-DC 中最佳抗原呈递细胞功能不可或缺的先决条件，使这些细胞有资格作为潜在用于主动特异性免疫治疗的强大细胞试剂。
Dendritic cells (DC) can be activated by proinflammatory cytokines or upon toll-like receptor (TLR) triggering. These stimuli induce specific patterns of phenotypic modulation and gene expression profiles. We investigated whether TLR triggering represents an indispensable requirement for the induction of T cell responses by human DC generated upon culture of monocytes in the presence of granulocyte macrophage colony-stimulating factor and interferon-alpha (IFN-DC). As model stimulator we chose imidazoquinolone (3M-001), a synthetic TLR7 agonist used in the treatment of skin infections and tumors and as experimental adjuvant. At difference with DC generated upon culture of monocytes in the presence of granulocyte macrophage colony-stimulating factor and interleukin (IL-4) (IL-4-DC), IFN-DC display a semimature phenotype. Furthermore, IFN-DC, but not IL-4-DC are able to induce CD4(+) and CD8(+) T cell responses, in steady state, for example, in the absence of TLR triggering. 3M-001 treatment induces up-regulation of the surface expression of costimulatory molecules and "de novo" production of IL-12 and IL-6 in IFN-DC. However, TLR7 triggering fails to significantly enhance the capacity of IFN-DC to induce antigen-specific cytotoxic T lymphocytes and to stimulate allogeneic CD4(+) T cells. These data indicate that TLR engagement and IL-12 production do not represent indispensable prerequisites for optimal antigen-presenting cell function in IFN-DC, qualifying these cells as powerful cellular reagents of potential use in active specific immunotherapy.