A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells

被引:140
作者
Screpanti, V [1 ]
Wallin, RPA
Ljunggren, HG
Grandien, A
机构
[1] Univ Stockholm, Dept Immunol, Wenner Gren Inst, S-10691 Stockholm, Sweden
[2] Karolinska Inst, Ctr Microbiol & Tumor Biol, Stockholm, Sweden
[3] Huddinge Univ Hosp, Karolinska Inst, Dept Med, Ctr Infect Med, Stockholm, Sweden
关键词
D O I
10.4049/jimmunol.167.4.2068
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
NK cells provide a line of defense against tumors and virus-infected cells that have lost the expression of one or more MHC class I isoforms. Here, we investigate whether inhibitors of apoptosis can block the rejection of tumors mediated by NK cells, by introducing the long form of Fas-associated death domain-like IL-1 beta -converting enzyme-associated inhibitory protein (FLIPL) and poxvirus cytokine response modifier A (CrmA) into the MHC class I-deficient T lymphoma cell line RMA-S. RMA-S cells do not normally express Fas in vitro, and it was previously postulated that the rejection of these tumors by NK cells is strictly perforin dependent. We show that perforin-deficient NK cells directly mediate Fas up-regulation on RMA-S cells and thereafter kill the cells in a Fas-dependent manner, and that RMA-S FLIPL and RMA-S CrmA are protected from such killing. When injected in immunocompetent recipients, RMA-S cells up-regulate Fas, rendering in vivo-passed mock-transduced cells sensitive to Fas-mediated apoptosis. Moreover, RMA-S FLIPL and RMA-S CrmA cells establish aggressive tumors, in contrast to RMA-S mock cells that are rejected. These results demonstrate that FLIPL and CrmA function as tumor progression factors by protecting MHC class I-deficient tumors from rejection mediated by NK cells. Moreover, our data indicate that death receptor-mediated apoptosis has a more prominent role in the clearance of NK-sensitive tumors than previously suggested.
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收藏
页码:2068 / 2073
页数:6
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