医学免疫学课件：NK细胞记忆

1、NK细胞记忆OUTLINE背景知识固有免疫功能记忆功能小鼠实验证据鼠巨细胞病毒诱导细胞因子诱导半抗原诱导人研究进展BACKGROUNDNK细胞无需抗原预先刺激不发生体细胞基因重排，依赖于一定数量的NKRs缺乏RAG重组酶依赖的克隆性抗原受体以及非特异的细胞毒作用BACKGROUD记忆性NK细胞二硝基氟苯 接触性超敏反应模型无T、B淋巴细胞的小鼠仍可产生无T、B、NK细胞的小鼠不能产生EVIDENCE小鼠巨细胞病毒MCMV感染模型诱导抗原特异性的NK细胞记忆单纯细胞因子诱导NK细胞记忆半抗原诱导的肝脏特有NK细胞记忆MCMV-INDUCED50%NK细胞表面表达Ly49H，特异性识别MCMV的M

2、157糖蛋白增值1000倍，持续存在并表现为活化表型凋亡至初始数量更多的IFN-更迅速MCMV-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细胞种类比例扩增与否缺乏M157的巨细胞病毒感染没有扩增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不能扩增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受体激活STAT4激活转录因子Zbtb32拮抗

5、抑癌因子Blimp-1促进细胞增殖MCMV-INDUCED效应性NK细胞凋亡促活分子Bcl-2水平的降低促凋亡信号升高大多数细胞：破损的线粒体积累小部分细胞：诱导自噬，形成记忆性细胞MCMV-INDUCEDKLRG生成记忆细胞能力KLRG1：成熟NK细胞30%-50%，90-100%KLRG-1高，而SCA-1和CD27下调机体和病原体的相互作用非造血细胞上的Nod受体IL-15生成MCMV-INDUCED使用特定的细胞表面标志定义记忆性NK细胞：未完善！细胞表型与不同刺激有关CD69、CD43、KLRG1、Ly49H较高CD27较低记忆NK细胞比初始NK细胞更成熟CYTOKINE-INDUC

6、ED体外IL-12、IL-18预活化的NK细胞荧光蛋白标记7-22天之后仍可检测体外二次刺激更强的免疫应答CYTOKINE-INDUCED无更强的细胞毒性对流感合胞病毒刺激产生免疫应答不具有抗原特异性辐射条件下，过继传输过经白细胞介素12/18和15预活化的NK细胞的小鼠具有更强的抗肿瘤能力HAPTEN-INDUCED半抗原致敏4-7天后重复刺激RAG缺陷型：可以产生免疫应答RAG和IL2受体链双缺陷：不能产生免疫应答传输已被致敏的NK细胞：恢复肝脏HAPTEN-INDUCED肝脏？趋化因子受体CXCR6CXCL16：肝窦内皮细胞维持肝脏记忆性NK细胞的定居和生存，但与抗原识别无关HAPTEN

7、-INDUCEDHUMANNK细胞特异性缺陷将会导致机体无法控制病毒的感染HCMV、EB、单纯疱疹病毒、水痘-带状疱疹病毒、人乳头瘤病毒NKG2ChighCD57+NK细胞只发生在曾感染过巨细胞病毒的个体中HUMAN缺乏NKG2C的人体内抗巨细胞病毒IgG滴度增加：NK细胞功能异常免疫反应并未完全失效，可能NK细胞上还有其他受体代偿机制HUMAN更广泛的免疫应答流感疫苗非同源性流感病毒感染时，不能够诱导足够多的可交叉反应性的CD8 T细胞产生应答流感疫苗免疫后人NK细胞能够短暂上调IFN-的表达SUMMARY现阶段已有的研究成果人类疾病的防治癌症的治疗仍不明确的受体分子和作用通路人类领域应用角

8、度考虑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

9、 the innate immune response required for responses to antigen skin challenge. J. Immunol. 182, 59495959.Klose, C.S., Flach, M., Mo hle, L., Rogell, L., Hoyler, T., Ebert, K., Fabiunke, C., Pfeifer, D., Sexl, V., Fonseca-Pereira, D., et al. (2014). Differentiation of type 1 ILCs from a common progeni

10、tor to all helper-like innate lymphoid cell lineages. Cell 157, 340356.Kondo, M., Weissman, I.L., and Akashi, K. (1997). Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661672.Kuijpers, T.W., Baars, P.A., Dantin, C., van den Burg, M., van Lier, R.A., and Roosn

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

12、 killer cells. Nature 342, 803805.Lee, J., Zhang, T., Hwang, I., Kim, A., Nitschke, L., Kim, M., Scott, J.M., Kamimura, Y., Lanier, L.L., and Kim, S. (2015). Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals. Immunity 42, 4

13、31442.Levy, E.M., Roberti, M.P., and Mordoh, J. (2011). Natural killer cells in human cancer: from biological functions to clinical applications. J. Biomed. Biotechnol. 2011, 676198.Lopez-Verge s, S., Milush, J.M., Pandey, S., York, V.A., Arakawa-Hoyt, J., Pircher, H., Norris, P.J., Nixon, D.F., and Lanier, L.L. (2010). CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset. Blood 116, 38653874.Lopez-Verge s, S., Milush, J.M., Schwartz, B.S., Pando, M.J., Jarjoura, J.,York, V.A., Houchin