醫(yī)學(xué)免疫學(xué)課件：NK細(xì)胞記憶

1、NK細(xì)胞記憶OUTLINE背景知識(shí)固有免疫功能記憶功能小鼠實(shí)驗(yàn)證據(jù)鼠巨細(xì)胞病毒誘導(dǎo)細(xì)胞因子誘導(dǎo)半抗原誘導(dǎo)人研究進(jìn)展BACKGROUNDNK細(xì)胞無(wú)需抗原預(yù)先刺激不發(fā)生體細(xì)胞基因重排，依賴于一定數(shù)量的NKRs缺乏RAG重組酶依賴的克隆性抗原受體以及非特異的細(xì)胞毒作用BACKGROUD記憶性NK細(xì)胞二硝基氟苯 接觸性超敏反應(yīng)模型無(wú)T、B淋巴細(xì)胞的小鼠仍可產(chǎn)生無(wú)T、B、NK細(xì)胞的小鼠不能產(chǎn)生EVIDENCE小鼠巨細(xì)胞病毒MCMV感染模型誘導(dǎo)抗原特異性的NK細(xì)胞記憶單純細(xì)胞因子誘導(dǎo)NK細(xì)胞記憶半抗原誘導(dǎo)的肝臟特有NK細(xì)胞記憶MCMV-INDUCED50%NK細(xì)胞表面表達(dá)Ly49H，特異性識(shí)別MCMV的M

2、157糖蛋白增值1000倍，持續(xù)存在并表現(xiàn)為活化表型凋亡至初始數(shù)量更多的IFN-更迅速M(fèi)CMV-INDUCEDTimothyE. OSullivan, JosephC. Sun, LewisL. Lanier Natural Killer Cell Memorynull, Volume 43, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013MCMV-INDUCEDTimothyE. OSullivan, JosephC. Sun, LewisL. Lanier Natural Killer Cell Memorynull, Volume 4

3、3, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013MCMV-INDUCEDTimothyE. OSullivan, JosephC. Sun, LewisL. Lanier Natural Killer Cell Memorynull, Volume 43, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013嵌合小鼠NK細(xì)胞種類比例擴(kuò)增與否缺乏M157的巨細(xì)胞病毒感染沒(méi)有擴(kuò)增MCMV-INDUCEDTimothyE. OSullivan, JosephC. Sun, LewisL. Lan

4、ier Natural Killer Cell Memorynull, Volume 43, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013缺少DNAM-1、PKC和Fyn不能擴(kuò)增MCMV-INDUCEDTimothyE. OSullivan, JosephC. Sun, LewisL. Lanier Natural Killer Cell Memorynull, Volume 43, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013IL-12受體激活STAT4激活轉(zhuǎn)錄因子Zbtb32拮抗

5、抑癌因子Blimp-1促進(jìn)細(xì)胞增殖MCMV-INDUCED效應(yīng)性NK細(xì)胞凋亡促活分子Bcl-2水平的降低促凋亡信號(hào)升高大多數(shù)細(xì)胞：破損的線粒體積累小部分細(xì)胞：誘導(dǎo)自噬，形成記憶性細(xì)胞MCMV-INDUCEDKLRG生成記憶細(xì)胞能力KLRG1：成熟NK細(xì)胞30%-50%，90-100%KLRG-1高，而SCA-1和CD27下調(diào)機(jī)體和病原體的相互作用非造血細(xì)胞上的Nod受體IL-15生成MCMV-INDUCED使用特定的細(xì)胞表面標(biāo)志定義記憶性NK細(xì)胞：未完善！細(xì)胞表型與不同刺激有關(guān)CD69、CD43、KLRG1、Ly49H較高CD27較低記憶NK細(xì)胞比初始NK細(xì)胞更成熟CYTOKINE-INDUC

6、ED體外IL-12、IL-18預(yù)活化的NK細(xì)胞熒光蛋白標(biāo)記7-22天之后仍可檢測(cè)體外二次刺激更強(qiáng)的免疫應(yīng)答CYTOKINE-INDUCED無(wú)更強(qiáng)的細(xì)胞毒性對(duì)流感合胞病毒刺激產(chǎn)生免疫應(yīng)答不具有抗原特異性輻射條件下，過(guò)繼傳輸過(guò)經(jīng)白細(xì)胞介素12/18和15預(yù)活化的NK細(xì)胞的小鼠具有更強(qiáng)的抗腫瘤能力HAPTEN-INDUCED半抗原致敏4-7天后重復(fù)刺激RAG缺陷型：可以產(chǎn)生免疫應(yīng)答RAG和IL2受體鏈雙缺陷：不能產(chǎn)生免疫應(yīng)答傳輸已被致敏的NK細(xì)胞：恢復(fù)肝臟HAPTEN-INDUCED肝臟？趨化因子受體CXCR6CXCL16：肝竇內(nèi)皮細(xì)胞維持肝臟記憶性NK細(xì)胞的定居和生存，但與抗原識(shí)別無(wú)關(guān)HAPTEN

7、-INDUCEDHUMANNK細(xì)胞特異性缺陷將會(huì)導(dǎo)致機(jī)體無(wú)法控制病毒的感染HCMV、EB、單純皰疹病毒、水痘-帶狀皰疹病毒、人乳頭瘤病毒NKG2ChighCD57+NK細(xì)胞只發(fā)生在曾感染過(guò)巨細(xì)胞病毒的個(gè)體中HUMAN缺乏NKG2C的人體內(nèi)抗巨細(xì)胞病毒IgG滴度增加：NK細(xì)胞功能異常免疫反應(yīng)并未完全失效，可能NK細(xì)胞上還有其他受體代償機(jī)制HUMAN更廣泛的免疫應(yīng)答流感疫苗非同源性流感病毒感染時(shí)，不能夠誘導(dǎo)足夠多的可交叉反應(yīng)性的CD8 T細(xì)胞產(chǎn)生應(yīng)答流感疫苗免疫后人NK細(xì)胞能夠短暫上調(diào)IFN-的表達(dá)SUMMARY現(xiàn)階段已有的研究成果人類疾病的防治癌癥的治療仍不明確的受體分子和作用通路人類領(lǐng)域應(yīng)用角

8、度考慮REFERENCEKeppel, M.P., Yang, L., and Cooper, M.A. (2013). Murine NK cell intrinsic cytokine-nduced memory-like responses are maintained following homeostatic proliferation. J. Immunol. 190, 47544762.Kish, D.D., Li, X., and Fairchild, R.L. (2009). CD8 T cells producing IL-17 and IFN-gamma initiate

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11、ek, E. (2008). Human NK cells can control CMV infection in the absence of T cells. Blood 112, 914915.Lanier, L.L. (2005). NK cell recognition. Annu. Rev. Immunol. 23, 225274.Lanier, L.L., Yu, G., and Phillips, J.H. (1989). Co-association of CD3 zeta with a receptor (CD16) for IgG Fc on human natural

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