Stimulation of CD8+ T cells following diphtheria toxin-mediated antigen delivery into dendritic cells.
Stimulation of CD8+ T cells following diphtheria toxin-mediated antigen delivery into dendritic cells.
复制标题
白喉毒素介导的抗原递送至树突状细胞后刺激 CD8 T 细胞。
DOI：
10.1128/iai.74.2.1001-1008.2006
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发表时间：
2006
影响因子：
3.1
通讯作者：
Starnbach,MichaelN
中科院分区：
文献类型：
--
作者：
Shaw,ChristineA;Starnbach,MichaelN
许多细胞内病原体的识别和清除需要CD 8 +T淋巴细胞的活化和随后的效应子功能。为了通过免疫刺激CD 8 +T细胞，必须将靶抗原递送到宿主细胞的胞质溶胶中。在那里，它们可以被加工成肽，并在主要组织相容性复合物I类分子的背景下呈递给抗原特异性CD 8 +T细胞。将抗原递送到胞质溶胶中的一种方法是将它们融合到能够进入哺乳动物细胞的修饰的细菌毒素中。毒素受体在宿主中的表达模式将决定毒素融合蛋白靶向的细胞群体，并因此将抗原特异性T细胞识别限制于相同群体。在这项研究中，我们描述了白喉毒素（DT）为基础的抗原输送系统的发展和特点。使用在树突状细胞（DC）中表达DT受体的CD 11 c-DTR转基因小鼠，该系统允许将CD 8 + T细胞抗原靶向递送至DC。我们发现，抗原特异性CD 8 +T细胞增殖的CD 11 c-DTR小鼠免疫后，与催化失活的DT-抗原融合蛋白。我们还表明，限制抗原递送至DC的基于毒素的系统比不限制递送至特定细胞类型的基于毒素的系统导致更稳健的抗原特异性CD 8 + T细胞增殖。这些结果对疫苗设计具有意义，并且它们表明使用基于毒素的载体将抗原靶向DC可能是诱导CD 8 + T细胞应答的有效方法。
Recognition and clearance of many intracellular pathogens requires the activation and subsequent effector functions of CD8+T lymphocytes. To stimulate CD8+T cells by immunization, the target antigens must be delivered into the cytosol of host cells. There they can be processed into peptides and presented in the context of major histocompatibility complex class I molecules to antigen-specific CD8+T cells. One method of delivering antigens into the cytosol is to fuse them to modified bacterial toxins that are able to enter mammalian cells. The expression pattern of the toxin receptors in the host will determine the cell population that the toxin fusion protein targets and will thus restrict antigen-specific T-cell recognition to the same population. In this study we describe the development and characterization of a diphtheria toxin (DT)-based antigen delivery system. Using CD11c-DTR transgenic mice that express the DT receptor in dendritic cells (DC), this system allows for targeted delivery of CD8+T-cell antigen to DC. We show that antigen-specific CD8+T cells proliferate in CD11c-DTR mice following immunization with catalytically inactive DT-antigen fusion proteins. We also show that a toxin-based system that restricts antigen delivery to DC results in more robust antigen-specific CD8+T-cell proliferation than a toxin-based system that does not restrict delivery to a particular cell type. These results have implications for vaccine design, and they suggest that use of a toxin-based vector to target antigen to DC may be an effective way to induce a CD8+T-cell response.