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首页> 外文学位 >Resurrecting the dead: Dendritic cells cross-present antigen derived from apoptotic cells, and induce viral- and tumor-specific cytotoxic T lymphocytes.
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Resurrecting the dead: Dendritic cells cross-present antigen derived from apoptotic cells, and induce viral- and tumor-specific cytotoxic T lymphocytes.

机译：使死者复活：树突状细胞交叉呈递来自凋亡细胞的抗原，并诱导病毒和肿瘤特异性的细胞毒性T淋巴细胞。

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Classically, CTLs are activated by antigens endogenously expressed by professional antigen presenting cells (APCs), processed and presented as peptide-MHC class I complexes. However, there is evidence for an exogenous pathway, whereby antigens that are not expected to gain access to the cytoplasm of an APC are indeed presented on MHC class I---the most dramatic example being the in vivo phenomenon of 'cross-priming.' My work has focused on two unanswered questions relevant to this important, but poorly defined pathway. These include the identity of the APC mediating the cross-presentation of antigen, and the mechanism whereby such antigens are acquired. We have found that human dendritic cells (DCs), but not macrophages, efficiently present antigen derived from apoptotic influenza infected cells, thus allowing for the induction of class I-restricted influenza-specific CD8+ CTLs. Interestingly, only antigenic material derived from apoptotic but not from necrotic cells are capable of charging the DCs. We have documented by immunofluorescence that it is the immature DC that is capable of efficiently engulfing apoptotic bodies/cells/corpses. And in the context of a maturation signal, these DCs will cross-present the apoptotic derived antigenic material on class I MHC leading to the induction of CD8+ T cells. While macrophages efficiently engulf apoptotic cells, they are not capable of cross-priming CTLs. This striking distinction has been correlated with the discovery that DCs and macrophages employ different receptors in the engagement and internalization of apoptotic cells.; As an in vivo example of this apoptosis-dependant exogenous pathway for loading MHC I and activating killer T cells, we investigated the mechanism by which patients with paraneoplastic cerebellar degeneration (PCD) mount an immune response to their tumors. We provide the first evidence for naturally occurring killer T-cell mediated tumor immunity in patients with ovarian and breast cancer. Additionally, we offer a mechanism by which such tumor-specific T cells might be activated---DCs capturing apoptotic tumor cells likely cross-present tumor antigen and activate tumor-specific killer T cells. This novel pathway defines a mechanism by which human DCs, a potent APC, acquire antigens from tumors, transplants, infected cells or even self tissue for the stimulation or tolerization of CTLs.
机译：经典地，CTL被专业抗原呈递细胞（APC）内源性表达的抗原激活，被加工并以肽-MHC I类复合物的形式呈现。但是，有证据表明存在外源性途径，据此，预期不会获得进入APC胞质通道的抗原的确存在于MHC I类上-最生动的例子是“交叉引发”的体内现象。 '我的工作集中在与这一重要但定义不明确的途径有关的两个未解决的问题。这些包括介导抗原交叉呈递的APC的身份，以及获得此类抗原的机制。我们发现人类树突状细胞（DCs），而不是巨噬细胞，有效地呈递来自凋亡型流感感染细胞的抗原，从而允许诱导I类限制性流感特异性CD8 + CTL。有趣的是，只有来自凋亡细胞而不是来自坏死细胞的抗原性物质才能够给DC充电。我们已经通过免疫荧光证明，未成熟的DC能够有效地吞噬凋亡小体/细胞/尸体。在成熟信号的背景下，这些DC将交叉呈递I类MHC上的凋亡来源抗原物质，从而诱导CD8 + T细胞。尽管巨噬细胞有效吞噬凋亡细胞，但它们不能交叉引发CTL。这种惊人的区别与DC和巨噬细胞在凋亡细胞的参与和内化过程中采用不同受体的发现有关。作为体内用于加载MHC I和激活杀伤性T细胞的依赖凋亡的外源途径的体内实例，我们研究了副肿瘤小脑变性（PCD）患者对其肿瘤产生免疫应答的机制。我们为卵巢癌和乳腺癌患者中自然发生的杀伤性T细胞介导的肿瘤免疫提供了第一个证据。此外，我们提供了一种机制，通过这种机制可以激活此类肿瘤特异性T细胞-捕获凋亡肿瘤细胞的DC可能交叉存在肿瘤抗原并激活肿瘤特异性杀伤性T细胞。这种新颖的途径定义了一种机制，人DCs（一种有效的APC）通过该机制从肿瘤，移植物，感染的细胞甚至自身组织中获取抗原，以刺激或耐受CTL。

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