Selective suicide of cross-presenting CD8+ dendritic cells by cytochrome c injection shows functional heterogeneity within this subset
Selective suicide of cross-presenting CD8+ dendritic cells by cytochrome c injection shows functional heterogeneity within this subset
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DOI：
10.1073/pnas.0712394105
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发表时间：
2008-02-26
影响因子：
11.1
通讯作者：
Lew, Andrew M.
中科院分区：
文献类型：
--
作者：
Lin, Ming Lee;Zhan, Yifan;Lew, Andrew M.
交叉呈现是激活CD8(+)T细胞的一种基本途径。到目前为止，这一概念在体内的应用有限，并且对CD8(+)树突状细胞(DC)专化这一任务的机制还不完全清楚。在此，我们利用交叉提呈树突状细胞的胞浆输出特性和胞浆细胞色素c(Cytc)的特性，选择性地启动交叉提呈树突状细胞中APAF-1依赖的细胞凋亡。一次静脉注射。在B6小鼠体内注射细胞色素C可使脾CD8(+)树突状细胞数量减少2-3倍，但在APAF-1缺陷小鼠中未见。体内和体外的功能研究表明，Cytc通过其对交叉呈递的DC的凋亡抑制作用，深刻地抑制了OVA特异性CD8(+)T细胞的增殖。更重要的是，体内注射Cytc可阻断细胞毒性T淋巴细胞对外源性抗原的诱导，降低后续对肿瘤攻击的免疫力。此外，只有部分表达丰富的IL-12和Toll样受体3的CD8(+)DC是有效的交叉呈现者。我们的数据支持这样的假设，即体内的交叉呈现需要胞内蛋白的胞浆转移，使部分CD8(+)树突状细胞具有交叉呈现的特化。我们认为，没有这种转移能力的DC，即使在CD8(+)DC亚群中，也不能交叉呈现。我们的模型开辟了一条在体内特异性靶向交叉递呈DC的途径，用于操纵针对感染、肿瘤和移植的细胞毒性T淋巴细胞反应。
Cross-presentation as a fundamental pathway of activating CD8(+) T cells has been well established. So far the application of this concept in vivo is limited, and the mechanisms that specialize CD8(+) dendritic cells (DCs) for this task are not fully understood. Here we take advantage of the specific cytosolic export feature of cross-presenting DCs together with the property of cytosolic cytochrome c (cyt c) in initiating Apaf-1-dependent apoptosis selectively in cross-presenting DCs. A single i.v. injection of cyt c in B6 mice produced a 2- to 3-fold reduction in splenic CD8(+) DCs but not in Apaf-1-deficient mice. Functional studies both in vivo and in vitro showed that cyt c profoundly abrogated OVA-specific CD8(+) T cell proliferation through its apoptosis-inclucing effect on cross-presenting DCs. More importantly, in vivo injection of cyt c abolished the induction of cytotoxic T lymphocytes to exogenous antigen and reduced subsequent immunity to tumor challenge. in addition, only a proportion of CD8(+) DCs that express abundant IL-12 and Toll-like receptor 3 were efficient cross-presenters. Our data, support the hypothesis that cross-presentation in vivo requires cytosolic diversion of endocytosed proteins, conferring cross-presentation specialization to a proportion of CD8(+) DCs. We propose that DCs incapable of such transfer, even within the CD8(+) DC subset, are unable to cross-present. Our model opens an avenue to specifically target cross-presenting DCs in vivo for manipulating cytotoxic T lymphocyte responses toward infections, tumors, and transplants.