Bracci Laura, Schumacher Reto, Provenzano Maurizio, Adamina Michel, Rosenthal Rachel, Groeper Celia, Zajac Paul, Iezzi Giandomenica, Proietti Enrico, Belardelli Filippo, Spagnoli Giulio C
Institute for Surgical Research and Hospital Management, DBM, University Hospital, Basel, Switzerland.
J Immunother. 2008 Jun;31(5):466-74. doi: 10.1097/CJI.0b013e318174a52a.
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.
树突状细胞（DC）可被促炎细胞因子激活，或在Toll样受体（TLR）触发后被激活。这些刺激诱导特定的表型调节模式和基因表达谱。我们研究了TLR触发对于在粒细胞巨噬细胞集落刺激因子和干扰素-α（IFN-DC）存在下培养单核细胞产生的人DC诱导T细胞反应是否是不可或缺的条件。作为模型刺激物，我们选择了咪唑喹啉酮（3M-001），一种用于治疗皮肤感染和肿瘤以及作为实验佐剂的合成TLR7激动剂。与在粒细胞巨噬细胞集落刺激因子和白细胞介素（IL-4）（IL-4-DC）存在下培养单核细胞产生的DC不同，IFN-DC表现出半成熟表型。此外，在稳态下，例如在没有TLR触发的情况下，IFN-DC能够诱导CD4+和CD8+ T细胞反应，但IL-4-DC不能。3M-001处理可诱导IFN-DC中共刺激分子表面表达上调以及IL-12和IL-6的“从头”产生。然而，TLR7触发未能显著增强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产生并非IFN-DC中最佳抗原呈递细胞功能的不可或缺的先决条件，这使这些细胞成为在主动特异性免疫治疗中潜在有用的强大细胞试剂。
