The heat shock protein HSP70 promotes mouse NK cell activity against tumors that express inducible NKG2D ligands
The heat shock protein HSP70 promotes mouse NK cell activity against tumors that express inducible NKG2D ligands
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DOI：
10.4049/jimmunol.179.8.5523
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发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Dressel, Ralf
中科院分区：
文献类型：
--
作者：
Elsner, Leslie;Muppala, Vijayakumar;Dressel, Ralf
应激诱导热休克蛋白（HSP） 70被认为是一种内源性危险信号，可以增加肿瘤的免疫原性并诱导CTL反应。我们在这项研究中发现，HSP70还能激活小鼠NK细胞，使其识别肿瘤细胞上应激诱导的NKG2D配体。在T细胞和B细胞缺陷的SCID小鼠中，发现过表达hsp70的人黑色素瘤细胞的肿瘤大小和转移率降低，但在缺乏额外功能性NK细胞的SCID/beige小鼠中则没有。在hsp70过表达的SCID小鼠肿瘤中，NK细胞被激活，从而杀死表达NKG2D配体的离体肿瘤细胞。在肿瘤中，发现了MHC I类链相关（MIC） A和B分子的表达。有趣的是，在SCID中，与对照肿瘤相比，在hsp70过表达的肿瘤中观察到MICA/B表达的反选择，而在SCID/beige小鼠中则没有，这表明MICA/B表达与功能相关。发现黑色素瘤细胞释放外泌体。与来自对照细胞的hsp70阴性外泌体相比，来自过表达hsp70的细胞的hsp70阳性外泌体能够在体外激活小鼠NK细胞，杀死组成性表达NKG2D配体的YAC-1细胞或诱导MICA/B表达的人类黑色素瘤细胞。因此，HSP70和诱导的NKG2D配体协同促进小鼠NK细胞的激活，从而减少肿瘤生长和抑制转移性疾病。
The stress-inducible heat shock protein (HSP) 70 is known to function as an endogenous danger signal that can increase the immunogenicity of tumors and induce CTL responses. We show in this study that HSP70 also activates mouse NK cells that recognize stress-inducible NKG2D ligands on tumor cells. Tumor size and the rate of metastases derived from HSP70-overexpressing human melanoma cells were found to be reduced in T and B cell-deficient SCID mice, but not in SCID/beige mice that lack additionally functional NK cells. In the SCID mice with HSP70-overexpressing tumors, NK cells were activated so that they killed ex vivo tumor cells that expressed NKG2D ligands. In the tumors, the MHC class I chain-related (MIC) A and B molecules were found to be expressed. Interestingly, a counter selection was observed against the expression of MICA/B in HSP70-overexpressing tumors compared with control tumors in SCID, but not in SCID/beige mice, suggesting a functional relevance of MICA/B expression. The melanoma cells were found to release exosomes. HSP70-positive exosomes from the HSP70-overexpressing cells, in contrast to HSP70-negative exosomes from the control cells, were able to activate mouse NK cells in vitro to kill YAC-1 cells, which express NKG2D ligands constitutively, or the human melanoma cells, in which MICA/B expression was induced. Thus, HSP70 and inducible NKG2D ligands synergistically promote the activation of mouse NK cells resulting in a reduced tumor growth and suppression of metastatic disease.