Elucidation of regulation of dendritic cells based on the real functional concept

众所周知，树突状细胞（dc）在抗肿瘤或感染的免疫防御中起着重要作用。然而，已经发现了许多由多种细胞因子主导的成熟或半成熟的树突状细胞。因此，需要明确树突状细胞功能成熟的精确概念。在目前的授权研究中，我们对这个课题有两个目标，建立“dc的功能成熟”。(1)原位诱导功能性dc建立治疗性肿瘤模型：为此，我们使用了NKT细胞作为细胞佐剂。我们发现NKT细胞配体负载的肿瘤细胞通过DC成熟导致体内先天免疫和适应性免疫。当我们原位分析DC时，我们发现这些DC捕获肿瘤细胞的碎片并经历成熟。相反，当我们使用CD40缺陷小鼠时，这种免疫被取消了。因此，通过CD40连接树突状细胞诱导原位功能成熟，功能成熟驱动对肿瘤细胞的强抗肿瘤作用。（II）为了阐明功能成熟，我们重点研究了精氨酸酶和吲哚胺2,3 -双加氧酶（IDO）这两个分子。两者都被认为是T细胞免疫的抑制因子。然而，根据我们的数据，精氨酸酶抑制剂在同种异体混合淋巴细胞试验（MLR）中对T细胞的DC刺激不起作用。另一方面，在TNF-α或IFN-γ或两者共同作用下，IDO在成熟dc中增强。这种炎症细胞因子诱导的成熟dc没有显示出强MLR，尽管PGE2单独不增强IDO，但PGE2与TNF-α或WN-γ一起增强了dc的IDO。这些结果表明，即使存在强烈的成熟刺激，MO的表达也可以在环境条件下增强，我们需要关注dc代谢物的成熟刺激。

It is well known that dendritic cells (DCs) play a role in the immune defense against tumor or infection. Howeve4 lots of mature or semi-mature DCs led by several kinds of cytokines have been identified. Therefore, to establish the precise concept of functional maturation of dendritic cell (DC) is required. In the current study under the granting, we have had two goals for this topic, establishment of "functional maturation of DCs".(I) Establishment of therapeutic tumor models by induction of functional DCs in situ: lb aim this, we used the cellular adjuvant by NKT cells. We found that administration of NKT cell ligand-loaded tumor cells led to innate immunity as well as adaptive immunity in vivo through DC maturation. When we analyzed DC in situ, we found that these DCs capture the debris of tumor cells and underwent the maturation. In contrast, when we used CD40 deficient mice, this immunity was abrogated. Thus, functional maturation in situ was induced by the CD40 ligation of DCs, and the functional maturation drives to the strong antitumor effect against tumor cells.(II) To elucidate the functional maturation, we have focused on the two molecules, that is arginase and indoleamine 2, 3-dioxygenase (IDO). Both have been known as suppressive factors for T cell immunity. Howeve4 from our data arginase inhibitor does not work for DC stimulation for T cells in allogeneic mixed lymphocyte assay (MLR) assays. On the other hand, IDO was enhanced in mature DCs led by TNF-α or IFN-γ or both. Such inflammatory cytokine-induced, mature DCs did not reveal the strong MLR Although PGE2 alone did not enhance IDO, PGE2 together with TNF-α or WN-γ enhanced IDO from DCs. In spite of them, this combination may lead the strong MLR These findings suggest that expression of MO can be enhanced under the condition from environment even in the presence of strong maturation stimuli and we need to pay attention for the maturation stimuli in terms of metabolite from DCs.