細(xì)胞生物學(xué)論文翻譯

1、細(xì)胞生物學(xué)論文翻譯生命科學(xué)學(xué)院0702班 舒曉 學(xué)號(hào)：2007114010223論文題目：Natural killer cells remember出處：Natural 457，544545（29 January 2009）作者：Sophie Ugolini and Eric Vivier原文：Cells of the adaptive immune system hold a grudge: on re-encountering a pathogen, they show a robust protective response. It seems that natural killer c

2、ells of the innate immune system might also have this ability.Learning, a hallmark of life, produces adaptation to new information. The immune system, like the nervous system, has this ability to learn from previous experience such as a single encounter with the many pathogens that exist. The result

3、 is immunological memory that confers long-lasting protection. For instance, once exposed to the measles virus in childhood, humans are immune to the disease for up to 75 years1. Until now, immunological memory was thought to be a feature of the adaptive immune system, specifically, of immune cells

4、called T and B cells. In this issue, however, Sun et al.2 (page 557) shed light on an unexpected player in the persistence of immunity: natural killer cells, which have traditionally been considered to be part of the innate immune system.Adaptive immunity appeared in vertebrates around 500 million y

5、ears ago3. In the more complex vertebrates, each clone of T and B cells expresses a unique cell-surface receptor, which preferentially recognizes a specific antigen and so, potentially, a specific invading pathogen. The ensemble of antigen-specific T- and B-cell receptors is called the immune repert

6、oire. When these receptors recognize and bind an antigen, the clones of T or B cells on which the receptors are expressed expand dramatically in number, and the cells acquire effector functions for example, T cells acquire the ability to kill the offending antigen-containing cells and B cells secret

7、e antibodies. Once the immune response is over, a contraction phase occurs, and only a small fraction of the expanded T- or B-cell population survives. These long-lived memory cells are central to maintaining long-term immunity after infection or vaccination. T and B cells are thus said to be adapti

8、ve, because their repertoire depends on an individuals antigenic history.Natural killer cells are classified as part of the innate immune system. Through many receptors, they recognize a vast array of mol- ecules, the expression of which is indicative of a particular situation, such as microbial inf

9、ection, tumour formation or DNA damage4. Sun et al.2 now show that natural killer cells also have properties previously ascribed only to T and B cells.In mice, a subset of natural killer cells, which express the Ly49H receptor on their surface (Ly49H+ cells), specifically recognize a protein produce

10、d by some strains of mouse cytomegalo- virus (MCMV)5,6. The specific recognition of these cells, an ability also shared by cells of the adaptive immune system5,6, allows Ly49H+ natural killer cells to limit MCMV infection at an early stage. But before infection, the number of Ly49H+ natural killer c

11、ells is much higher than the number of antigen-specific T cells (around half of all natural killer cells are Ly49H+, compared with between 1 in 104 and 1 in 108 T cells for a given T-cell clone before infection).Previous work 7 has shown that MCMV infection results in a two- to tenfold increase in t

12、he number of natural killer cells. To compare this response under conditions similar to that of a T-cell response, Sun et al. experimentally reduced the initial number of Ly49H+ natural killer cells. They found that these cells can proliferate extensively (up to 900-fold expansion), specifically in

13、response to MCMV. Once the infection had peaked, a contraction phase followed, with a subset of the virus-experi- enced Ly49H+natural killer cells surviving and maintaining the characteristics of an effector cell. Whats more, when the authors transferred these virus-experienced natural killer cells

14、to newborn immunodeficient mice, the cells were tenfold more protective against MCMV infection than their counterparts from uninfected mice (Fig. 1). Protection was correlated with a greater effector function of the virus-experienced natural killer cells in vitro, rather than with a higher prolifera

15、tion rate of these cells in vivo. So, as natural killer cells seem to retain information from a viral infection, Sun and colleaguesdata suggest the existence of memory natural killer cells.But whether the terms memory and naive (not previously exposed to an antigen), used for T and B cells, should a

16、lso be used for natural killer cells is debatable. Whereas clones of T and B cells express one antigen-specific type of receptor on their surface providing the basis for a specific memory response natural killer cells express an array of receptors with distinct specificities. So a natural killer cel

17、l that has been activated through one receptor could be reactivated via another receptor that recognizes an unrelated molecule. Sun et al. find that this is indeed the case when Ly49H+, virus-experienced natural killer cells are stimulated through another surface receptor, NK1.1 (Fig. 1). By contras

18、t, memory T and B cells show a strong response only to the specific antigen that initially triggered their expansion, or possibly to another antigen recognized by the same receptor a crossreactive antigen8.Experienced natural killer cells therefore preserve a more general memory of their previous st

19、imulation, and seem to show an enhanced response not just to the challenge that initially caused their expansion but also to those challenges that trigger other, unrelated receptors on their surface. So the phenomenon Sun et al. describe may be more related to a training of natural killer cells in e

20、ffector responses than to the responses of antigen- specific memory T and B cells.Earlier studies have already indicated that natural killer cells resemble T and B cells more closely than was originally appreciated9,10. In particular, they showed that these cells learn to recognize self 11 and are p

21、rimed by other immune cells such as dendritic cells12. If Sun and colleagues findings and these previous studies13 also hold true in other experimental systems, they would contribute to a blurring of the distinction between innate and adaptive immunity. The question then arises of whether this disti

22、nction is still a valid way of describing, understanding and predicting immune responses.Furthermore, Sun et al. observed a high rate of natural killer cell proliferation and the occurrence of long-lived cells of this type under conditions in which the initial number of virus-specific cells was arti

23、ficially lowered. Whether MCMV infection in unmanipulated mice generates long-lived natural killer cells with memory properties remains unknown. Also to be discovered is whether in vivo stimulation of natural killer cells with agents other than MCMV results in the generation of long-lived experience

24、d cells.Nonetheless, this study2 will undoubtedly prompt research into the mechanisms that allow the boosted effector function of natural killer cells to be maintained across cell divisions, in particular the epigenetic marks associated with various stages of these cellsactivation. As the nature of

25、reliable biological markers of protective immunity is still a matter of debate14, it is exciting to consider that natural killer cells might be monitored as a potential protection correlate for testing the efficiency of vaccines under development.譯文：自然殺傷細(xì)胞記憶適應(yīng)性免疫系統(tǒng)相關(guān)的細(xì)胞有一個(gè)特殊的記憶功能：在再次遇到的病原體的細(xì)胞中，他們表現(xiàn)出

26、強(qiáng)大的保護(hù)性反應(yīng)。由此推測(cè)，先天性免疫系統(tǒng)的自然殺傷細(xì)胞可能也有這個(gè)功能。在生命過程中通過不斷學(xué)習(xí)，不斷產(chǎn)生適應(yīng)環(huán)境變化的新信息是生命活動(dòng)的標(biāo)志。免疫系統(tǒng)，如同神經(jīng)系統(tǒng)一樣，在不斷遭遇各種病原體的過程中自身有了一種重要的經(jīng)驗(yàn)，它們不斷地遭遇新的病原體，同時(shí)不斷地學(xué)習(xí)。最后免疫記憶被賦予長期保護(hù)。類似于首次暴露在兒童體內(nèi)的麻疹病毒，人類對(duì)類似疾病的免疫長達(dá)75 年1。直到現(xiàn)在，免疫記憶被認(rèn)為是一個(gè)適應(yīng)性免疫系統(tǒng)的特征功能，尤其是免疫細(xì)胞，免疫T細(xì)胞和B細(xì)胞。在這個(gè)問題上，Sun等2（頁557）闡明了一個(gè)意想不到的持久性免疫的參與者：向來被認(rèn)為是先天免疫系統(tǒng)一部分的自然殺傷細(xì)胞。約5.0億年前，適

27、應(yīng)性免疫出現(xiàn)在脊椎動(dòng)物中3。對(duì)于更高等的脊椎動(dòng)物，每個(gè)增值的T細(xì)胞和B細(xì)胞都表達(dá)了一種獨(dú)特的細(xì)胞表面受體，這種受體優(yōu)先確認(rèn)一個(gè)特異抗原，所以，可能當(dāng)一個(gè)特定病原體入侵，共同作用的抗原特異性T和B被稱為免疫功能細(xì)胞。當(dāng)這些受體被識(shí)別而與抗原結(jié)合時(shí)，由于受體表達(dá)，T細(xì)胞或B細(xì)胞增值，數(shù)量急劇增加，細(xì)胞獲得效應(yīng)功能例如，T細(xì)胞獲得能力殺死犯錯(cuò)誤的抗原，B細(xì)胞分泌的抗體起免疫效應(yīng)。一旦免疫反應(yīng)結(jié)束，在'收縮'階段，只有一小部分或B細(xì)胞存活。這些壽命長的記憶細(xì)胞是機(jī)體保持長期感染或疫苗接種后的免疫力的中心。因?yàn)門細(xì)胞和B細(xì)胞潛在的功能依賴于他們獨(dú)特的接受抗原刺激的經(jīng)驗(yàn)，因此說他們具有適應(yīng)

28、性。自然殺傷細(xì)胞被列為先天免疫系統(tǒng)的一部分。通過許多受體，它們識(shí)別到種類繁多的各種分子，這些分子各自的表達(dá)都表示一個(gè)特殊情況，如細(xì)菌性感染，腫瘤的形成或DNA 的損傷4。而今Sun 等2也表明，自然殺傷細(xì)胞也有以前只歸咎于T細(xì)胞和B細(xì)胞的這種特性。在小鼠體內(nèi)，自然殺傷細(xì)胞的表面表達(dá)的Ly49H受體（Ly49H +細(xì)胞），特異性識(shí)別某些菌株對(duì)小鼠巨細(xì)胞病毒（小鼠巨細(xì)胞病毒）5,6產(chǎn)生的蛋白質(zhì)。這些細(xì)胞具體的識(shí)別，使適應(yīng)性免疫系統(tǒng)細(xì)胞也有這種能力5,6，使Ly49H +自然殺傷細(xì)胞在早期階段限制小鼠巨細(xì)胞病毒感染。但在感染之前Ly49H +自然殺傷細(xì)胞的數(shù)目遠(yuǎn)遠(yuǎn)高于抗原特異性T細(xì)胞的數(shù)量（約所有一

29、半的自然殺傷細(xì)胞為Ly49H +，相較而言在感染之前于104或108 個(gè)T細(xì)胞中有一個(gè)給定細(xì)胞增值）。早期的研究顯示，小鼠巨細(xì)胞病毒感染使自然殺傷細(xì)胞的數(shù)量成2-10倍的增加。將其與同等條件下T細(xì)胞受刺激后的反應(yīng)相比，Sun等實(shí)驗(yàn)性地減少了一些初級(jí)的Ly49H + 自然殺傷細(xì)胞，結(jié)果他們發(fā)現(xiàn)，這些細(xì)胞能夠廣泛增殖（高達(dá)900次增值）特異性應(yīng)答小鼠巨細(xì)胞病毒感染。一旦感染達(dá)到高峰，一個(gè)收縮階段尾隨而至，根據(jù)所謂的'病毒經(jīng)驗(yàn)'Ly49H +自然殺傷細(xì)胞存活下來保持相應(yīng)效應(yīng)細(xì)胞的特征參數(shù)。更重要的是，一旦將這些擁有病毒經(jīng)驗(yàn)的自然殺傷細(xì)胞移植到新生的免疫缺陷型小鼠體內(nèi)，對(duì)于小鼠巨細(xì)胞病

30、毒性感染，這些移植了相應(yīng)自然殺傷細(xì)胞的小鼠就比同樣但是未移植該自然殺傷細(xì)胞的小鼠多了10倍多的保護(hù)能力（圖1所示）。相關(guān)的保護(hù)是因?yàn)橛?#39;病毒經(jīng)驗(yàn)'自然殺傷細(xì)胞的廣泛受體反映，而不是這些細(xì)胞較高的增殖率。Sun 和他同事的實(shí)驗(yàn)數(shù)據(jù)材料暗示了自然殺傷細(xì)胞記憶的存在。但是否記憶和原始（以前沒有暴露在抗原下的）這種為T細(xì)胞和B細(xì)胞所適用的說法也應(yīng)該適用于自然殺傷細(xì)胞是有爭(zhēng)議的。而相對(duì)于克隆的T細(xì)胞和B細(xì)胞表達(dá)一種抗原表面特定類型的受體-提供一個(gè)特定的記憶應(yīng)答，自然殺傷細(xì)胞表達(dá)一系列具有鮮明特點(diǎn)的受體。這樣一來，已通過一個(gè)受體激活的自然殺傷細(xì)胞可以通過另一種不同的受體分子再度激活。Sun

31、等發(fā)現(xiàn)這是個(gè)真實(shí)的情況：具有病毒經(jīng)驗(yàn)的Ly49H +自然殺傷細(xì)胞可通過另一種表面受體被激活NK1.1（圖1）。相比之下，記憶T細(xì)胞和B細(xì)胞只對(duì)最初引發(fā)增值的特定抗原有強(qiáng)烈的應(yīng)答，也可能對(duì)由同一受體承認(rèn)的另一種抗原交叉抗原8有強(qiáng)烈反應(yīng)。經(jīng)驗(yàn)豐富的自然殺傷細(xì)胞，因此廣泛保留早期的一般的刺激信息，似乎不僅對(duì)早期引起他們?cè)鲋车拇碳け憩F(xiàn)出更強(qiáng)的反應(yīng)而且對(duì)這些觸發(fā)其他無關(guān)的表面受體的刺激它們也表現(xiàn)出更強(qiáng)的應(yīng)答。因此，Sun 等描述的現(xiàn)象可能更類似于自然殺傷細(xì)胞對(duì)感受應(yīng)答方面的培訓(xùn)，而不是抗原特異性記憶T細(xì)胞和B細(xì)胞的應(yīng)答。早先的研究已經(jīng)表明，自然殺傷細(xì)胞與T細(xì)胞和B細(xì)胞的聯(lián)系比最初的發(fā)現(xiàn)看起來更緊密9，1

32、0。特別是，他們發(fā)現(xiàn)這些細(xì)胞學(xué)會(huì)認(rèn)識(shí)自我11并得到其他免疫細(xì)胞的引物，如樹突狀細(xì)胞12。如果Sun和他的同事的研究結(jié)果和以前的這些研究13還持有其他實(shí)驗(yàn)系統(tǒng)實(shí)現(xiàn)，將有助于他們找出先天免疫和適應(yīng)性免疫之間模糊的區(qū)別。而隨之而來的問題是，這種區(qū)別是否仍然是一個(gè)描述、了解和預(yù)測(cè)免疫反應(yīng)的有效途徑。 此外，Sun等觀察到的自然殺傷細(xì)胞的高增殖率和在早期病毒特異性細(xì)胞不正常減少的情形下自然殺傷細(xì)胞的長壽命細(xì)胞的發(fā)生。是否長壽命的記憶性能的自然殺傷細(xì)胞是在小鼠巨細(xì)胞病毒感染小鼠中產(chǎn)生的仍然不得而知。同時(shí)待發(fā)現(xiàn)的還包括其中起主要作用的是以因子強(qiáng)烈刺激的自然殺傷細(xì)胞還是因小鼠巨細(xì)胞病毒而產(chǎn)生的擁有豐富經(jīng)驗(yàn)的長

33、壽命細(xì)胞。然而，這些研究2無疑將促使我們進(jìn)一步研究在細(xì)胞分裂時(shí)保持推動(dòng)自然殺傷細(xì)胞感受功能的機(jī)制，尤其是與這些細(xì)胞各個(gè)階段的活化有關(guān)的表觀遺傳標(biāo)記。作為可靠的保護(hù)性免疫的生物標(biāo)志物的性質(zhì)仍然是一個(gè)有爭(zhēng)論的問題14，令人高興的是，自然殺傷細(xì)胞可以作為一個(gè)相關(guān)潛在的保護(hù)監(jiān)測(cè)測(cè)試正在開發(fā)的疫苗效率。 作者簡(jiǎn)介：Sophie Ugolini and Eric Vivier are in the Centre dImmunologie de Marseille-Luminy, Université de la Méditerranée, INSERM, CNRS, Camp

34、usde Luminy, case 906, 13288 Marseille cedex 9, France, and in the Faculté de Médecine-Timone, Marseille, France.e-mails: ugoliniciml.univ-mrs.fr; vivierciml.univ-mrs.fr引用： 1. Gourley, T. S. et al. Semin. Immunol. 16, 323333 (2004).2. Sun, J. C., Beilke, J.N.&Lanier,L.L.Nature 457, 557

35、561 (2009).3. Pancer, Z. & Cooper, M. D. Annu.Rev.Immunol.24,497518 (2006).4. Vivier, E. et al. Nature Immunol. 9, 503510 (2008).5. Smith, H. R.et al.Proc.Natl Acad. Sci.USA 99, 88268831 (2002).6. Arase, H. et al. Science 296, 13231326 (2002).7. Dokun, A. O. et al. Nature Immunol. 2, 951956 (200

36、1).8. Selin, L. K. et al. Immunol. Rev. 211, 164181 (2006).9. Glas, R. et al. J. Exp. Med. 191, 129138 (2000).10.Raulet, D. H. Nature Immunol. 5, 9961002 (2004).11.Raulet,D. H. & Vance, R.E.Nature Rev.Immunol.6,520531 (2006).12.Lucas, M. et al. Immunity 26, 503517 (2007).13.Vivier, E. & Mali

37、ssen, B. Nature Immunol. 6, 1721 (2005).14.Zinkernagel,R.M. &Hengartner,H.Immunol. Rev.211,310319(2006).附：自然殺傷細(xì)胞自然殺傷（natural killer，NK）細(xì)胞在早期一直是個(gè)功能的概念，起因于該類細(xì)胞可在無預(yù)先致敏時(shí)殺傷某些血液系統(tǒng)腫瘤和一些變異轉(zhuǎn)化細(xì)胞。通常認(rèn)為NK細(xì)胞殺傷靶細(xì)胞的過程為“MHC非限制性”，原因在于NK細(xì)胞的靶細(xì)胞可以為同基因、異基因、甚至可以無MHC表達(dá)，從而認(rèn)為NK細(xì)胞是機(jī)體抗感染抗腫瘤的第一道天然防線。（一）NK細(xì)胞的來源及組織分布 NK細(xì)胞的前體為

38、造血干細(xì)胞，在骨髓中分化為淋巴類祖細(xì)胞后從骨髓直接進(jìn)入外周血。骨髓中的NK細(xì)胞很少有殺傷功能，具殺傷功能的NK細(xì)胞主要存在于外周血中。與T細(xì)胞相比NK的發(fā)育不需要胸腺的存在，與B細(xì)胞相比NK的成熟不需要生發(fā)中心的存在。由于NK細(xì)胞不表達(dá)T淋巴細(xì)胞和B淋巴細(xì)胞所具有的抗原識(shí)別受體（TCR或BCR）及其它特有標(biāo)志，NK細(xì)胞曾被稱為“裸細(xì)胞”而列為第三類淋巴細(xì)胞。又由于NK細(xì)胞較T細(xì)胞和B細(xì)胞體積為大，胞漿中富含噬苯胺藍(lán)顆粒，又被稱“大顆粒淋巴細(xì)胞”。當(dāng)NK細(xì)胞被激活后，其形態(tài)會(huì)發(fā)生改變，顆粒明顯增多，這些顆粒與其殺傷過程有關(guān)。外周血及其器官中的成熟NK細(xì)胞主要承擔(dān)殺傷效應(yīng)細(xì)胞的功能，因而可以根據(jù)N

39、K細(xì)胞對(duì)某些腫瘤細(xì)胞（如人的K562、小鼠YAC-1）的殺傷力強(qiáng)弱來判斷其天然殺傷功能。 人和小鼠的NK細(xì)胞主要分布于外周血、脾和肝。人外周血中NK細(xì)胞約占淋巴細(xì)胞總數(shù)的5%7%。成年人或動(dòng)物的肝、肺、腹腔、呼吸道黏膜和消化道黏膜上皮等均存在具有天然殺傷功能的MK細(xì)胞。人肝含大量CD56+細(xì)胞，其含量可達(dá)肝總淋巴細(xì)胞的50%以上，其中CD56+CD3NK細(xì)胞>30%，CD56+CD3+細(xì)胞（后稱為NKT細(xì)胞）>25%，二者總和（25*109細(xì)胞）已遠(yuǎn)遠(yuǎn)超出外周血中NK細(xì)胞的總數(shù)（后者<1*109細(xì)胞）。肝有可能是機(jī)體最大的專職天然免疫功能的器官。（二）NK細(xì)胞的表面標(biāo)志與分類

40、 雖然NK細(xì)胞有不少表面標(biāo)志（表面受體或表面抗原、分子等），但多為與其他免疫細(xì)胞共有。目前僅把人類NK細(xì)胞的CD56分子和小鼠NK細(xì)胞的NK1.1及LY49等分子作為較為特異的NK細(xì)胞表面標(biāo)志。NK細(xì)胞的判斷需依據(jù)：（1）NK細(xì)胞較為特異的陽性表面標(biāo)志：如人類NK細(xì)胞的CD56和小鼠NK細(xì)胞的NK1.1等；（2）NK細(xì)胞的陰性表面標(biāo)志：有些表面標(biāo)志為其它淋巴細(xì)胞所特有，但不存在于NK細(xì)胞表面，如T細(xì)胞受體（TCR）、免疫球蛋白分子、CD3和CD4分子等；（3）NK細(xì)胞的功能：NK細(xì)胞具有以MHC非限制性方式直接殺傷某些靶細(xì)胞這一特有的功能，在人的NK細(xì)胞表面有免疫球蛋白FC受體（CD16），并

41、能介導(dǎo)ADCC效應(yīng)。 NK細(xì)胞是異質(zhì)性細(xì)胞群體，其亞群的分類至今仍無國際公認(rèn)的標(biāo)準(zhǔn)。近年來通過對(duì)NK細(xì)胞的表面標(biāo)志和分泌因子、粘附功能等進(jìn)行深入研究，發(fā)現(xiàn)了許多具有特異性表型和功能的亞群，由此將NK細(xì)胞進(jìn)行了分類。 以表面標(biāo)志為依據(jù)將NK細(xì)胞分為CD56bright和CD56dim兩個(gè)亞群。NK細(xì)胞表達(dá)眾多表面分子，如CD56、CD16、CD57、CD161等，但這些表面標(biāo)志都不是NK細(xì)胞所特有的，只具有相對(duì)特異性。通常將CD56+、CD16+、CD3、TCR、BCR的淋巴細(xì)胞認(rèn)為是NK細(xì)胞，并以CD56的表達(dá)密度不同，將NK細(xì)胞分為CD56bright和CD56dim兩群。CD56brigh

42、tNK細(xì)胞高表達(dá)CD56、CD94/NKG2A和CD62L；低表達(dá)CD16、KIR；表達(dá)高親和力的IL-2受體。而CD56dimNK細(xì)胞高表達(dá)CD16、PEN5、KIR、LFA-1；低表達(dá)CD56、CD94/NKG2A；僅表達(dá)中親和力的IL-2受體。 以細(xì)胞因子分泌為依據(jù)將NK細(xì)胞分為NK1和NK2兩個(gè)亞群。CD4+Th細(xì)胞可以分為Th1和Th2兩種亞群，NK細(xì)胞也存在類似的亞群。分離外周血CD16+或CD56+細(xì)胞，用IL-12和抗IL-4抗體可以誘導(dǎo)出分泌IFN的Th1型NK亞群，用IL-4和抗IL-12抗體誘導(dǎo)出分泌IL-5、IL-13的Th2型NK細(xì)胞亞群，分別命名為NK1和NK2。也

43、有人認(rèn)為NK細(xì)胞發(fā)育經(jīng)歷NK2NK0NK1的過程。在這一過程中IL-4促進(jìn)NK-2增殖；IL-12促進(jìn)NK2向NK1轉(zhuǎn)變，并促進(jìn)NK1的成熟。 以粘附功能為依據(jù)將NK細(xì)胞分為粘附NK（A-NK）和非粘附NK（NA-NK）兩個(gè)亞群。NK細(xì)胞在IL-2的誘導(dǎo)下表現(xiàn)出對(duì)實(shí)體表面的粘附能力，由此可將NK細(xì)胞分為粘附NK（A-NK）和非粘附NK（NA-NK）兩個(gè)亞群。A-NK細(xì)胞表面的表型比較均一，主要為CD3CD56dimCD16+IL-2R+，不含CD56bright細(xì)胞。NA-NK細(xì)胞是具有不同表型的異質(zhì)性群體，CD56bright、CD56dim、CD56、CD16+、CD16均能出現(xiàn)。（三）N

44、K細(xì)胞的受體與識(shí)別 TCR和BCR介導(dǎo)T、B細(xì)胞的識(shí)別活化是現(xiàn)代免疫學(xué)研究的核心內(nèi)容之一，比TCR和BCR更為復(fù)雜的是NK細(xì)胞的受體，迄今為止，已發(fā)現(xiàn)有數(shù)十種之多，分屬抑制性受體和活化性受體兩大類，各大類又包括數(shù)個(gè)家族，體現(xiàn)了NK細(xì)胞受體的多樣性，介導(dǎo)了NK細(xì)胞的不同識(shí)別模式，分別傳遞不同的活化信號(hào)和抑制信號(hào)，各種信號(hào)在細(xì)胞表面的整合，在細(xì)胞內(nèi)部的傳遞，最終賦予NK細(xì)胞發(fā)揮多種生物學(xué)效應(yīng)。（四）NK細(xì)胞的生物學(xué)功能 二十多年前幾家實(shí)驗(yàn)室的學(xué)者們?cè)谘芯縏細(xì)胞對(duì)靶細(xì)胞的特異性殺傷時(shí)同時(shí)發(fā)現(xiàn)正常對(duì)照組大鼠或小鼠的脾細(xì)胞可以像腫瘤免疫小鼠的脾細(xì)胞一樣殺傷某些腫瘤細(xì)胞，繼而在正常人外周血發(fā)現(xiàn)淋巴細(xì)胞可以

45、殺傷某些癌癥來源的癌細(xì)胞或培養(yǎng)的癌細(xì)胞，從而將NK細(xì)胞作為監(jiān)控早期變異細(xì)胞的免疫監(jiān)視體系之一，進(jìn)一步研究發(fā)現(xiàn)NK細(xì)胞不僅殺傷腫瘤細(xì)胞，而且對(duì)病毒感染細(xì)胞亦具有清除作用。近年又發(fā)現(xiàn)NK細(xì)胞可以殺傷并清除潛伏有胞內(nèi)菌的自體單核細(xì)胞，NK細(xì)胞也可通過快速而有效地分泌細(xì)胞因子，活化并聚集大量的中性粒細(xì)胞，從而抵抗真菌類的感染。這些功能證明NK細(xì)胞在機(jī)體的防御體系中有重要作用，NK細(xì)胞的缺失將引起機(jī)體產(chǎn)生腫瘤或病原體感染。NK細(xì)胞與病毒感染和腫瘤靶細(xì)胞密切接觸后，可通過釋放穿孔素、顆粒酶、表達(dá)FasL和分泌TNF產(chǎn)生細(xì)胞殺傷作用。（1）NK細(xì)胞殺傷腫瘤細(xì)胞。NK細(xì)胞分布于機(jī)體全身，無T細(xì)胞所具備的CD3和TCR，以MHC非限制性方式殺傷腫瘤細(xì)胞。NK細(xì)胞不經(jīng)過胸腺即可成熟，無胸腺的裸鼠和SCID鼠體內(nèi)NK細(xì)胞多于一