Optimal stimulation for CD70 induction on human monocyte-derived dendritic cells and the importance of CD70 in naive CD4+T-cell differentiation
Optimal stimulation for CD70 induction on human monocyte-derived dendritic cells and the importance of CD70 in naive CD4+T-cell differentiation
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DOI：
10.1111/j.1365-2567.2010.03220.x
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发表时间：
2010-05-01
期刊：
影响因子：
6.4
通讯作者：
Uchiyama, Takashi
中科院分区：
文献类型：
--
作者：
Arimoto-Miyamoto, Kazue;Kadowaki, Norimitsu;Uchiyama, Takashi
小鼠研究表明，树突状细胞（DC）上的CD 70足以将T细胞耐受转化为免疫，从而诱导抗肿瘤免疫应答。因此，重要的是研究（i）在广泛用于肿瘤免疫治疗的人单核细胞衍生的DC（MoDC）上诱导CD 70的最佳刺激，和（ii）CD 70在用MoDC刺激的初始CD 4+和CD 8 + T细胞的功能分化中的作用。我们表明，干扰素-α（IFN-α）是一个关键的细胞因子，分化成DC的单核细胞的能力，表达CD 70成熟后。IFN-α诱导的MoDC上的CD 70表达由不同类别的成熟诱导因子（Toll样受体配体、CD 40配体和促炎介质）引起，其中前列腺素E-2最有效。用MoDC刺激的幼稚T细胞也表达CD 70。用MoDC刺激促进幼稚CD 4 + T细胞以CD 70依赖性方式获得产生T辅助细胞1型和2型细胞因子的能力。相反，CD 70-CD 27相互作用减少了免疫调节细胞因子IL-10的产生。在用MoDC刺激期间，CD 27信号在幼稚CD 8 + T细胞中的效应分子的诱导中不起主导作用。这项研究增加了一个新的功能，通用的细胞因子，I型IFN，即诱导CD 70的MoDC。CD 70在与MoDC刺激期间通过DC-T细胞和T细胞-T细胞相互作用促进初始CD 4 + T细胞获得免疫刺激活性。因此，CD 70-CD 27相互作用可能在基于DC的免疫治疗中诱导有效的免疫应答中起重要作用。
P>Studies in mice have shown that CD70 on dendritic cells (DCs) is sufficient to convert T-cell tolerance into immunity and hence induce anti-tumour immune responses. Therefore, it is important to investigate (i) optimal stimuli to induce CD70 on human monocyte-derived DCs (MoDCs), which are widely used for tumour immunotherapy, and (ii) the role of CD70 in functional differentiation of naive CD4+ and CD8+ T cells stimulated with MoDCs. We show that interferon-alpha (IFN-alpha) is a key cytokine to differentiate monocytes into DCs with the capacity to express CD70 upon maturation. CD70 expression on IFN-alpha-induced MoDCs was elicited by different categories of maturation-inducing factors (Toll-like receptor ligands, CD40 ligand and pro-inflammatory mediators), among which prostaglandin E-2 was most effective. Naive T cells stimulated with MoDCs also expressed CD70. Stimulation with MoDCs promoted naive CD4+ T cells to acquire the ability to produce T helper type 1 and 2 cytokines in a CD70-dependent manner. In contrast, the CD70-CD27 interaction diminished the production of an immunoregulatory cytokine IL-10. The CD27 signal did not play a dominant role in the induction of effector molecules in naive CD8+ T cells during the stimulation with MoDCs. This study adds a novel function to the versatile cytokines, type I IFNs, that is, the induction of CD70 on MoDCs. CD70 promotes naive CD4+ T cells to acquire immunostimulatory activity through the DC-T-cell and T-cell-T-cell interactions during the stimulation with MoDCs. Hence, the CD70-CD27 interaction may play an important role in inducing effective immune responses in DC-based immunotherapy.