Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+NK cells in healthy humans
Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+NK cells in healthy humans
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DOI：
10.1111/cei.12785
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发表时间：
2016-08-01
影响因子：
4.6
通讯作者：
Simpson, R. J.
中科院分区：
文献类型：
--
作者：
Bigley, A. B.;Rezvani, K.;Simpson, R. J.
巨细胞病毒（CMV）感染可显著扩增NKG2C+/NKG2A- NK细胞，而NKG2C+/NKG2A- NK细胞是表达人白细胞抗原(HLA)- e的感染细胞的有效杀手。由于HLA-E在几种血液学恶性肿瘤中也过表达，并且巨细胞病毒与白血病复发风险降低有关，我们确定了潜伏巨细胞病毒感染对NK细胞对四种不同水平HLA-E表达的肿瘤靶细胞系的细胞毒性的影响。NK细胞对K562（白血病来源）和U266（多发性骨髓瘤来源）靶细胞的细胞毒性在健康cmv血清阳性供者中显著高于血清阴性供者，并且与靶细胞HLA-E和NK细胞NKG2C表达密切相关。NK细胞对转染HLA-E的淋巴瘤靶细胞（221.AEH）的细胞毒性在CMV组中大约高出三倍，而NK细胞对未转染的721.221细胞的细胞毒性在CMV组之间相同。NK细胞脱颗粒（CD107a(+)）和干扰素(IFN)-产生至221。AEH细胞几乎完全定位于NKG2C亚群，抗体阻断NKG2C完全消除了CMV对NK细胞抗221的细胞毒性作用。AEH细胞。此外,221年。AEH饲养细胞和白细胞介素(IL)-15可优先扩增cmv血清阴性供体的NKG2C(+)/NKG2A(-) NK细胞，并增加NK细胞对HLA-E+肿瘤细胞系的细胞毒性。我们得出结论，潜伏CMV感染通过NKG2C(+) NK细胞的积累增强NK细胞的细胞毒性，这可能有助于防止以高HLA-E表达为特征的血液恶性肿瘤的发生和发展。
Cytomegalovirus (CMV) infection markedly expands NKG2C+/NKG2A- NK cells, which are potent killers of infected cells expressing human leucocyte antigen (HLA)-E. As HLA-E is also over-expressed in several haematological malignancies and CMV has been linked to a reduced risk of leukaemic relapse, we determined the impact of latent CMV infection on NK cell cytotoxicity against four tumour target cell lines with varying levels of HLA-E expression. NK cell cytotoxicity against K562 (leukaemia origin) and U266 (multiple myeloma origin) target cells was strikingly greater in healthy CMV-seropositive donors than seronegative donors and was associated strongly with target cell HLA-E and NK cell NKG2C expression. NK cell cytotoxicity against HLA-E transfected lymphoma target cells (221.AEH) was approximate to threefold higher with CMV, while NK cell cytotoxicity against non-transfected 721.221 cells was identical between the CMV groups. NK cell degranulation (CD107a(+)) and interferon (IFN)- production to 221.AEH cells was localized almost exclusively to the NKG2C subset, and antibody blocking of NKG2C completely eliminated the effect of CMV on NK cell cytotoxicity against 221.AEH cells. Moreover, 221.AEH feeder cells and interleukin (IL)-15 were found to expand NKG2C(+)/NKG2A(-) NK cells preferentially from CMV-seronegative donors and increase NK cell cytotoxicity against HLA-E+ tumour cell lines. We conclude that latent CMV infection enhances NK cell cytotoxicity through accumulation of NKG2C(+) NK cells, which may be beneficial in preventing the initiation and progression of haematological malignancies characterized by high HLA-E expression.