Adam Christian, King Susan, Allgeier Thomas, Braumüller Heidi, Lüking Carolin, Mysliwietz Josef, Kriegeskorte Anja, Busch Dirk H, Röcken Martin, Mocikat Ralph
GSF-Institut für Molekulare Immunologie, Marchioninistr. 25, D-81377 München, Germany.
Blood. 2005 Jul 1;106(1):338-44. doi: 10.1182/blood-2004-09-3775. Epub 2005 Mar 15.
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 (NK) 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 inter-feron-gamma expression and involved priming endogenous DCs for interleukin-12 production. Our data suggest a novel pathway linking innate and adaptive immunity.
普遍认为，抗肿瘤CD8+细胞毒性T淋巴细胞（CTL）的启动需要CD4+ T细胞提供的帮助。我们发现，树突状细胞（DC）与自然杀伤（NK）细胞之间的相互作用可以在CTL诱导过程中绕过T辅助细胞环节。骨髓来源的DC能够引发A20淋巴瘤的排斥反应并诱导肿瘤特异性长期记忆，尽管它们并未负载肿瘤衍生抗原。使用CD40基因敲除小鼠和细胞清除实验表明，这种效应并不需要CD4+细胞。初次排斥反应和长期CTL记忆均是DC激活NK细胞的结果。初次排斥反应所必需的NK细胞毒性取决于肿瘤细胞上自然杀伤细胞组2 D（NKG2D）配体的表达。使用NKG2D四聚体阻断这些配体可在体外和体内消除肿瘤杀伤作用。长期反应是由于CTL针对A20和体外分化DC上表达的抗原。导致不依赖CD4+辅助细胞的CTL反应的机制被阐明为一个由NK细胞激活引发的级联反应。该途径依赖于γ干扰素的表达，并涉及启动内源性DC产生白细胞介素-12。我们的数据提示了一条连接固有免疫和适应性免疫的新途径。
