[雙語(yǔ)翻譯]---醫(yī)學(xué)外文翻譯--腫瘤免疫中nk細(xì)胞功能的細(xì)胞因子驅(qū)使調(diào)（原文）

1、Cytokine-driven regulation of NK cell functions in tumor immunity: Role of the MICA-NKG2D systemNorberto W. Zwirner *, Mercedes B. Fuertes, Mar? ´a Victoria Girart, Carolina I. Domaica, Lucas E. RossiLaboratorio de

2、Inmunogene ´tica, Hospital de Cl? ´nicas ‘‘Jose ´ de San Mart? ´n’’, and Departamento de Microbiolog? ´a, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaAvailable onlin

3、e 26 February 2007AbstractNatural killer (NK) cells are critical players during tumor growth control in immunocompetent hosts. These cells also establish a cross-talk with dendritic cells (DCs) and promote a Th1-mediated

4、 immunity. NKG2D is a pivotal receptor that directs the tumoricidal activity of NK cells through the recognition of a group of ligands such as MICA widely expressed on different tumors. Here we will review the most impor

5、tant tumor immune escape mechanisms that compromise the functionality of NKG2D and its cognate ligands, including TGF-b secretion, tumor shedding of soluble MICA, and additional mechanisms that compromise the tumoricidal

6、 activity of NKG2D-expressing cells. Such mechanisms may also dampen the cross-talk between NK cells and DCs during the anti-tumor immune responses. Recent knowledge may lead to innovative approaches to promote efficient

7、 NK cell-mediated anti-tumor immune responses. # 2007 Elsevier Ltd. All rights reserved.Keywords: MHC; NKG2D; NK cells; MICA; Tumor1. IntroductionTumor transformation and growth is a multi-step process that involves the

8、accumulation of mutations and results in a genetic instability, loss of cell cycle control, resistance to apoptosis, unlimited self-renewal capacity and the selection of tumor variants with the ability to invade local an

9、d distant tissues. However, in immunocompetent hosts tumors are forced to grow under the permanent pressure of an immune system that imposes an immunological pressure. This observation has led to the postulation of the i

10、mmunosur- veillance hypothesis. Currently, we know that many immune-mediated cell destruction mechanisms are activated to eliminate tumor cells. The progress made during the lasttwo decades in the area of cellular and mo

11、lecular immunology and oncology has greatly contributed to a deeper knowledge about the tumor-host relationship. New ideas have been proposed to explain the complex nature of the effect of the immune system on the tumor

12、cells and the mechanisms developed by tumors to escape different immune effector mechanisms. Although not mutually exclusive, two main lines of thinking were postulated [1,2]. In the first case, it was proposed that tumo

13、r growth is a consequence of an immunoediting process achieved by the immune system on tumor cells [1]. Accordingly, tumor growth and metastasis in immunocompetent hosts is a consequence of three stages (the ‘‘three Es’’

14、 of immunoedit- ing). First, the immune system achieves elimination of susceptible tumor cells (immunosurveillance). Secondly, equilibrium between the immune system and the surviving (resistant) tumor cells is reached, t

15、hus sculpting the tumor phenotype. Finally, surviving tumor cells enter the tumor escape phase that is often accompanied by the establishment of metastasis. Other authors have proposed that tumors growwww.elsevier.com/lo

16、cate/cytogfrCytokine fax: +54 11 5950 8758. E-mail address: nwz@sinectis.com.ar (N.W. Zwirner).1359-6101/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.cytogfr.2007.01.013the ability of NKG

17、2D engagement alone to trigger IFN-g secretion has been questioned by the observation that engagement of this receptor by some solid-phase-immobi- lized NKG2D-specific mAbs could elicit cytotoxic granule release and targ

18、et cell killing but not IFN-g secretion [13,16,19,23]. In some cases, this differential response has been attributed to a differential splicing of NKG2D in mouse but not human NK cells and to a differential association w

19、ith the DAP10 and DAP12 adapter proteins [24,25]. However, recent experimental evidence indicates that mouse NKG2D associates with both adapter proteins in NK cells to trigger an activation signal [26]. In some cases, th

20、e discrepancy in the ability of NKG2D to promote IFN-g secretion might be due to the use of solid phase-immobilized mAbs against NKG2D since in these experiments, IFN-g secretion was induced by engagement of NKG2D with s

21、olid phase- immobilized chimeric molecules that resemble NKG2DLs, such as MICA-Fc and ULBP1-Fc [16]. In addition, it is likely that in order to trigger IFN-g secretion through NKG2D, NK cells require the co-engagement of

22、 other receptors [12,13,23]. Therefore, interpretation of the results obtained upon stimulation of NK cells through NKG2D during the initiation of cytotoxicity and cytokine production should be cautious considering that

23、the distinct outcomes depend on the cell type, activation state of the cells, species analyzed (human or mouse) and the specific ligand being tested. Two populations of human NK cells have been identified. The major popu

24、lation (about 90%) is cytotoxic and shows a CD56dimCD16+ phenotype, whereas the remaining 10% of the NK cells are a source of immunoregulatory cytokines and present a CD56brightCD16dim or CD56brightCD16?phenotype [27]. A

25、lthough NKG2D expression seems to be slightly higher in CD56dim than in CD56bright NK cells, these differences do not appear to be involved in the differential IFN-g production and proliferation of these NK cell subsets

26、upon activation by dendritic cells (DCs) [28]. In humans and mice, NKG2D is promiscuous in terms of ligand recognition. Human NKG2D ligands (NKG2DLs) are the MHC class I related-chain genes A and B (MICA and MICB) [15],

27、and a group of glycosylphosphatidylinositol (GPI)-bound surface molecules called UL16 binding protein (ULBP)-1, -2, -3 and -4 [18,29]. Mice have a different set of NKG2DLs, which comprise the retinoic acid early inducibl

28、e gene (Rae)-1 family (a group of GPI-anchored, cell surface glycoprotein), the minor histocompatibility antigen H60 (an integral transmembrane proteins), and the murine UL16- binding protein-like transcript 1 (MULT-1, a

29、ll of which exhibit low sequence homology with their human counter- parts [18,29]. However, human NKG2D binds mouse NKG2DLs and mouse NKG2D can recognize some human NKG2DLs, most likely reflecting a selective advantage o

30、f preserving the NKG2D receptor in both species. The MICA and MICB genes were described in 1994 as a group of genes that map within the MHC class I region, but exhibit a low homology with the classical MHC class I genes[

31、30,31]. Expression of MICA has been observed in human epithelial and fibroblast cell lines [32,33], in primary cultures of endothelial cells and fibroblasts [34], tumors of different histotypes [12,35], thymic medulla [3

32、6], and gastrointestinal epithelium [32]. Expression of MICA was also observed in cultured human keratinocytes [37], but this expression was not observed on the cell surface [34]. Also, activated CD4+ and CD8+ T cells we

33、re shown to express MICA [38–40], although low levels of this NKG2DL are expressed on the cell surface [41]. The generalized expression of MICA observed in many tumors [35,42–46] suggests that its expression is a consequ

34、ence of the malignant neotransformation. However, recent evidence indicates that expression of MICA and other NKG2DLs is induced by the DNA damage pathway in response to genotoxic insults, which is a critical step during

35、 the neotransformation [47]. However, although the tumor suppressor p53 anti-oncogen has been involved in the protection against malign transformation [48], p53 does not appear to be involved in up-regulation of MICA and

36、 subsequent acquisition of susceptibility to NKG2D- mediated cytotoxicity. Also, expression of MICA in activated T cells indicates that this NKG2DL can also be induced by cell activation. Coincidentally, cell activation

37、and neotransformation are two cellular processes regulated by NF-kB [49]. Experimental evidence accumulated during the last years indicates that the MICA-NKG2D system participates in different aspects of the immune respo

38、nse [15,32,50–56], but that this interaction is particularly important during tumor immunity [42,43,57–60]. The anti-tumor effector mechanisms used by NK cells comprise the cytotoxicity against susceptible target cells a

39、nd the secretion of IFN-g and other proinflammatory cytokines. The mechanisms of NK cell-mediated cytotoxicity have been reviewed else- where [61,62]. In most cases, NK cells lyse susceptible target cells secreting cytot

40、oxic granules that contain granzymes and perforin. However, studies in perforin-, granzymes- or NK cell-deficient mice and studies with human cells revealed that NK cells can also lyse target cells by death receptor-medi

41、ated cytotoxicity such as the Fas- FasL system and the TNF-related apoptosis-inducing ligand (TRAIL) [63]. In mice, NK cell perforin-mediated cytotoxicity, but not production of IFN-g was critical for the rejection of Ra

42、e-1b-expressing tumor cells in vivo [22] and for the establishment of tumor metastasis [64], suggesting that perforin-granzyme secretion is the major effector mechanisms of the NKG2D-dependent, NK cell- mediated anti-tum

43、or response. Therefore, current evidence indicates that the mechanisms through which NKG2D triggers NK cell-mediated cytotoxicity relies on the granule secretion pathway, but it remains an open question whether NKG2D eng

44、agement can also elicit Fas- and TRAIL- mediated apoptosis of susceptible targets. The molecular dissection of receptors and effector molecules involved in NK cell-mediated tumor cell destruction may lead to theN.W. Zwir