Dendritic Cell Internalization of α-Galactosylceramide from CD8 T Cells Induces Potent Antitumor CD8 T-cell Responses
Dendritic Cell Internalization of α-Galactosylceramide from CD8 T Cells Induces Potent Antitumor CD8 T-cell Responses
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DOI：
10.1158/0008-5472.can-11-1459
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发表时间：
2011-12-15
期刊：
影响因子：
11.2
通讯作者：
Sung, Young Chul
中科院分区：
文献类型：
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作者：
Choi, Dong Hoon;Kim, Kwang Soon;Sung, Young Chul
树突状细胞（DC）将α-半乳糖神经酰胺（α GalCer）呈递给表达恒定T细胞受体的自然杀伤T细胞（iNKT），激活这些细胞以分泌多种细胞因子，这进而导致DC成熟和其他细胞类型（包括NK细胞、B细胞和常规T细胞）的激活。在这项研究中，我们表明，α GalCer脉冲抗原活化的CD 8 T细胞过继转移到荷瘤小鼠引起供体T细胞增殖，前体频率和细胞毒性淋巴细胞活性显着增加。这种效应是白细胞介素（IL）-2依赖性的，涉及自然杀伤T细胞（NKT）和DC，因为缺乏IL-2、NKT和DC的小鼠对过继转移的α GalCer负载的CD 8 T细胞缺乏任何增强的应答。iNKT活化通过将α GalCer从供体CD 8 T细胞的细胞膜转移到存在于宿主DC上的α GalCer受体CD 1d上来介导。aGalCer转移通过供体CD 8 T细胞的预先活化而增加，并且需要宿主DC的AP-2介导的内吞作用。此外，宿主iNKT细胞活化导致强IL-2合成，从而增加供体CD 8 T细胞的扩增和分化。这些细胞的转移导致对小鼠中已建立的实体瘤的治疗功效改善。因此，我们的发现说明了在体外抗原活化后CD 8 T细胞的α GalCer负载如何可以利用过继性T细胞疗法的治疗潜力。Cancer Res; 71（24）; 7442-51. (C)2011年AACR。
Dendritic cells (DC) present a-galactosylceramide (alpha GalCer) to invariant T-cell receptor-expressing natural killer T cells (iNKT) activating these cells to secrete a variety of cytokines, which in turn results in DC maturation and activation of other cell types, including NK cells, B cells, and conventional T cells. In this study, we showed that alpha GalCer-pulsing of antigen-activated CD8 T cells before adoptive transfer to tumor-bearing mice caused a marked increase in donor T-cell proliferation, precursor frequency, and cytotoxic lymphocyte activity. This effect was interleukin (IL)-2 dependent and involved both natural killer T cells (NKT) and DCs, as mice lacking IL-2, NKTs, and DCs lacked any enhanced response to adoptively transferred alpha GalCer-loaded CD8 T cells. iNKT activation was mediated by transfer of alpha GalCer from the cell membrane of the donor CD8 T cells onto the alpha GalCer receptor CD1d which is present on host DCs. aGalCer transfer was increased by prior activation of the donor CD8 T cells and required AP-2-mediated endocytosis by host DCs. In addition, host iNKT cell activation led to strong IL-2 synthesis, thereby increasing expansion and differentiation of donor CD8 T cells. Transfer of these cells led to improved therapeutic efficacy against established solid tumors in mice. Thus, our findings illustrate how alpha GalCer loading of CD8 T cells after antigen activation in vitro may leverage the therapeutic potential of adoptive T-cell therapies. Cancer Res; 71(24); 7442-51. (C) 2011 AACR.