DC-NK cell cross talk as a novel CD4+ T-cell-independent pathway for antitumor CTL induction
DC-NK cell cross talk as a novel CD4+ T-cell-independent pathway for antitumor CTL induction
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DOI：
10.1182/blood-2004-09-3775
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发表时间：
2005-07-01
期刊：
影响因子：
20.3
通讯作者：
Mocikat, R
中科院分区：
文献类型：
--
作者：
Adam, C;King, S;Mocikat, R
一般认为，抗肿瘤CD 8（+）细胞毒性T淋巴细胞（CTL）的启动需要CD 4（+）T细胞提供的帮助。我们发现，树突状细胞（DC）和自然杀伤（INK）细胞之间的相互作用可以绕过T辅助细胞的CTL诱导。骨髓来源的树突状细胞引起排斥的A20淋巴瘤和诱导肿瘤特异性的长期记忆，虽然他们没有加载肿瘤衍生的抗原。使用CD 40（-）敲除小鼠和细胞耗竭的实验表明，这种效应不需要CD 4（+）细胞。原发性排斥反应和长期CTL记忆都是DC激活NK细胞的结果。NK细胞的杀伤活性依赖于肿瘤细胞上自然杀伤组2D（NKG 2D）配体的表达，这是原发性排斥反应所必需的。使用NKG 2D四聚体阻断这些配体在体外和体内消除了肿瘤杀伤。长期应答是由于针对A20和体外分化的DC上表达的抗原的CTL。导致CD 4（+）辅助细胞非依赖性CTL应答的机制被阐明为由NK细胞激活启动的级联反应。该途径依赖于干扰素-γ的表达，并涉及引发内源性DC产生白细胞介素-12。我们的数据表明，一种新的途径连接先天免疫和适应性免疫。
It is generally accepted that priming of antitumor CD8(+) cytotoxic T lymphocytes (CTLs) needs help that can be provided by CD4(+) T cells. We show that interactions between dendritic cells (DCs) and natural killer (INK) cells can bypass the T helper arm in CTL induction. Bone marrow-derived DCs caused rejection of the A20 lymphoma and induced tumor-specific long-term memory, although they were not loaded with tumor-derived antigen. Experiments using CD40(-) knock-out mice and cell depletion showed that this effect did not require CD4(+) cells. Both primary rejection and long-term CTL memory were the result of NK cell activation by DCs. NK cytotoxicity, which was necessary for primary rejection, was dependent on expression of natural killer group 2 D (NKG2D) ligands on tumor cells. Blocking of these ligands using NKG2D tetramers abrogated tumor killing in vitro and in vivo. The long-term response was due to CTLs directed against antigen(s) expressed on A20 and in vitro-differentiated DCs. The mechanism leading to CD4(+) helper cell-independent CTL responses was elucidated as a cascade that was initiated by NK cell activation. This pathway was dependent on interferon-gamma expression and involved priming endogenous DCs for interleukin-12 production. Our data suggest a novel pathway linking innate and adaptive immunity.