Molecular and cellular requirements for enhanced antigen cross-presentation to CD8 cytotoxic T lymphocytes
Molecular and cellular requirements for enhanced antigen cross-presentation to CD8 cytotoxic T lymphocytes
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DOI：
10.4049/jimmunol.179.4.2310
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Podack, Eckhard R.
中科院分区：
文献类型：
--
作者：
Oizumi, Satoshi;Strbo, Natasa;Podack, Eckhard R.
MHC I类介导的APC对CD 8 T细胞的交叉致敏对于针对病毒感染和肿瘤的基于CTL的免疫至关重要。我们以前已经表明，肿瘤分泌的热休克蛋白gp 96-伴侣肽交叉引物CD 8 CTL，是真正的肿瘤抗原和代理，抗原OVA的特异性。我们现在表明，肿瘤分泌的热休克蛋白gp 96-伴侣肽提高了数百万倍的CD 8 CTL的Ag交叉引发的效率比单独的非伴侣蛋白的交叉引发活性。gp 96还充当非伴侣蛋白交叉引发的佐剂，但在这种能力下，gp 96的活性比作为肽伴侣低1000倍。从机制上讲，转染的肿瘤细胞原位分泌gp 96-IG募集并激活树突状细胞和NK细胞至gp 96释放位点，并促进局部CD 8 CTL扩增。Gp 96介导的CD 8 T细胞交叉致敏需要B7.1/2共刺激，但在没有NKT和CD 4细胞以及没有CD 40 L的情况下，在淋巴结缺陷小鼠中不受阻碍地进行。在淋巴结不存在的情况下，Gp 96驱动的CD 8 CTL的MHC I交叉引发为在gp 96释放位点产生局部的基于组织的CTL提供了新的机制。这一途径可能构成了一个至关重要的，早期检测和快速反应机制，是有效的实质组织对组织损伤抗原剂的防御。
MHC class I-mediated cross-priming of CD8 T cells by APCs is critical for CTL-based immunity to viral infections and tumors. We have shown previously that tumor-secreted heat shock protein gp96-chaperoned peptides cross prime CD8 CTL that are specific for genuine tumor Ags and for the surrogate, Ag OVA. We now show that tumor-secreted heat shock protein gp96-chaperoned peptides enhance the efficiency of Ag cross-priming of CD8 CTL by several million-fold over the cross-priming activity of unchaperoned protein alone. Gp96 also acts as adjuvant for cross-priming by unchaperoned proteins, but in this capacity gp96 is 1000-fold less active than as a peptide chaperone. Mechanistically, the in situ secretion of gp96-Ig by transfected tumor cells recruits and activates dendritic cells and NK cells to the site of gp96 release and promotes CD8 CTL expansion locally. Gp96-mediated cross-priming of CD8 T cells requires B7.1/2 costimulation but proceeds unimpeded in lymph node-deficient mice, in the absence of NKT and CD4 cells and without CD40L. Gp96-driven MHC I cross-priming of CD8 CTL in the absence of lymph nodes provides a novel mechanism for local, tissue-based CTL generation at the site of gp96 release. This pathway may constitute a critically important, early detection, and rapid response mechanism that is operative in parenchymal tissues for effective defense against tissue damaging antigenic agents.