医学免疫学课件：巨细胞病毒（CMV）诱导的自然杀伤（NK）细胞记忆

1、巨细胞病毒（CMV）诱导的自然杀伤（NK）细胞记忆提纲背景NK细胞NK细胞记忆的发现鼠巨细胞病毒（MCMV）诱导NK细胞记忆的机制激活与扩增凋亡与生存记忆前体的调控人巨细胞病毒（MCMV）诱导NK细胞记忆展望NK细胞直接杀伤被病毒感染的自身细胞或者肿瘤细胞属于固有免疫细胞反应快速应答模式和强度不因与病原微生物的反复接触而改变NK细胞记忆的发现半抗原二硝基氟苯 (DNFB)诱发的接触性超反应(Contact hypersensitivity ,CHS)模型野生型小鼠+DNFBCHS几周后+DNFB记忆性免疫应答无T、B细胞的小鼠+DNFBCHS几周后+DNFB记忆性免疫应答无T、B、NK细胞的小

2、鼠+DNFB无CHSDNFB 致敏的小鼠NK细胞CHSNK细胞记忆的发现Ly49H+ NK 细胞与MCMV Figure 1. Magnitude and Kinetics of CD8+ T Cell and NK Cell Memory Formation after InfectionUpon exposure to cognate antigen, naive CD8+ T cells clonally expand and differentiate into effector cells during the “expansion” phase. This first phase

3、is followed by.TimothyE. OSullivan, JosephC. Sun, LewisL. Lanier Natural Killer Cell Memorynull, Volume 43, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013NK细胞记忆的发现Ly49H+ NK 细胞与MCMV记忆NK细胞的特点：与记忆T细胞相像二次膨胀（secondary expansion）在体外时有更强的效应细胞功能增强对机体的保护，对抗病毒特异性缺失糖蛋白m157的MCMV不能引发这种反应MCMV诱导NK细胞记忆的机制：激活与扩增

4、凋亡与生存记忆前体的调控MCMV诱导NK细胞记忆的机制：激活与扩增 Figure 2. Activation of CD8+ T Cells and NK Cells during MCMV InfectionDuring viral infection, NK cells and CD8+ T cells mount specific responses after antigen receptor is triggered. TCR-MHC interactions (signal 1), co-stimulation (including CD28; signal 2), a.Timot

5、hyE. OSullivan, JosephC. Sun, LewisL. Lanier Natural Killer Cell Memorynull, Volume 43, Issue 4, 2015, 634645/10.1016/j.immuni.2015.09.013MCMV诱导NK细胞记忆的机制：激活与扩增Signal 1: Ly49H-m157相互作用嵌合小鼠致死剂量辐射小鼠，而后取不同的小鼠骨髓对其进行重建野生型骨髓：DAP12缺失型=1：n感染MCMV后Ly49H+ NK 细胞占大多数Ly49H+ NK 细胞初始比例越小，扩增幅度越大Ly49H- NK 细胞没有减少感染m157

6、缺失的MCMV后Ly49H+ NK 细胞比例并没有特殊变化MCMV诱导NK细胞记忆的机制：激活与扩增Signal 2: DNAM-1共刺激DNAM-1共刺激分子识别CD155、CD122等胞内信号转导区募集激酶DNAM-1-Fyn通路记忆细胞生成【必需】效应和记忆细胞扩增【非必需】DNAM-1-PKC通路记忆细胞生成【必需】效应细胞扩增【必需】通路具体机制不明MCMV诱导NK细胞记忆的机制：激活与扩增Signal 3: 炎性细胞因子细胞因子作用IL-12，转录因子STAT4NK细胞的激活，IFN-g生成IFN-gNK细胞扩增、分化（非自分泌途径）IL-33，IL-18，MyD88调控特异性NK

7、细胞的扩增IL-12，IL-18，type I IFNs增殖、保护作用AM Beaulieu et al. Nature Immunology 15, 546553 (2014) doi:10.1038/ni.2876 Zbtb32 regulates the proliferative burst of Ly49H-activated NK cells during MCMV infection.MCMV诱导NK细胞记忆的机制：凋亡与生存效应NK细胞凋亡下调促活分子Bcl-2上调Bim介导的促凋亡信号IL-15的作用保持过继转入的效应、记忆NK细胞数量抑制细胞凋亡线粒体的作用累积破损的线粒体

8、开始Bim介导的细胞凋亡记忆细胞通过自噬移除破损线粒体线粒体自噬受体BNIP3和BNIP3L效应T细胞如何存活机制不明MCMV诱导NK细胞记忆的机制：凋亡与生存IL-15的作用机制IL-15激活PI(3)kAkt磷酸化Foxo3a防止Bim转录上调激活Erk1/2Bim磷酸化的Bim被蛋白酶体降解限制Bim水平促表达Mcl-1Noxa拮抗拮抗Bcl-2相关蛋白A1microRNA-155抑制拮抗SOCS1激活MCMV诱导NK细胞记忆的机制：凋亡与生存效应NK细胞凋亡下调促活分子Bcl-2上调Bim介导的促凋亡信号IL-15的作用保持过继转入的效应、记忆NK细胞数量抑制细胞凋亡线粒体的作用累积破

9、损的线粒体开始Bim介导的细胞凋亡记忆细胞通过自噬移除破损线粒体线粒体自噬受体BNIP3和BNIP3LMCMV诱导NK细胞记忆的机制：记忆前体的调控外在环境因素KLRG1+ NK细胞与KLRG1- NK细胞KLRG1- NK细胞分裂能力更强，优先产生记忆细胞IL-15的作用机制细胞固有因素生成过程中RAG表达表面KLRG1少优先产生记忆细胞生成过程中RAG不表达表面KLRG1多高反应性，难存活不清楚产生记忆NK细胞的效应细胞是否有特殊marker Figure 7. Reciprocal Regulation of Memory NK Cell Progenitors by Commensal

10、 Bacteria and T CellsA Hypothetical ModelNod receptors on host nonhematopoietic cells sense commensal bacteria and enhance IL-15 production in myeloid cells. Competitive consumption of .Yosuke Kamimura, LewisL. Lanier Homeostatic Control of Memory Cell Progenitors in the Natural Killer Cell Lineagen

11、ull, Volume 10, Issue 2, 2015, 280291/10.1016/j.celrep.2014.12.025MCMV诱导NK细胞记忆的机制：记忆前体的调控外在环境因素KLRG1+ NK细胞与KLRG1- NK细胞KLRG1- NK细胞分裂能力更强，优先产生记忆细胞IL-15的作用机制细胞固有因素生成过程中RAG表达表面KLRG1少优先产生记忆细胞生成过程中RAG不表达表面KLRG1多高反应性，难存活不清楚产生记忆NK细胞的效应细胞是否有特殊marker Figure abstractJennyM. Karo, DavidG. Schatz, JosephC. Sun T

12、he RAG Recombinase Dictates Functional Heterogeneity and Cellular Fitness in Natural Killer Cellsnull, Volume 159, Issue 1, 2014, 94107/10.1016/j.cell.2014.08.026HCMV诱导NK细胞记忆NKG2C+NK细胞可能是NK细胞发挥记忆功能的主力激活、增殖信号HLA-EIL-12NKG2CCD57可以对某些病毒做出反应HBV、HCV、HIV可能受某些病毒影响孩童青少年、成年受体多样性改变？小结与展望许多作用机制尚不了解效应NK细胞是否像CD8

13、+T细胞一样有专门产生记忆细胞的？产生记忆细胞具体过程是怎样的？怎样将这些研究应用于临床？帮助获得性免疫功能不强的人对抗CMV？找到方法广泛提高人群免疫力？对于其他病原体NK细胞是否有类似机制？其他固有免疫细胞是否也有类似特性？参考文献OLeary, J.G., Goodarzi, M., Drayton, D.L., and von Andrian, U.H. (2006). T cell and B cellindependent adaptive immunity mediated by natural killer cells. NAT IMMUNOL 7, 507-516.Sun,

14、J.C., Beilke, J.N., and Lanier, L.L. (2009). Adaptive immune features of natural killer cells. Nature 457, 557561.Sun, J.C., Beilke, J.N., and Lanier, L.L. (2010). Immune memory redefined: characterizing the longevity of natural killer cells. Immunol. Rev. 236, 8394.Sun, J.C., Madera, S., Bezman, N.

15、A., Beilke, J.N., Kaplan, M.H., and Lanier, L.L. (2012). Proinflammatory cytokine signaling required for the generation of natural killer cell memory. J. Exp. Med. 209, 947954.Beaulieu, A.M., Zawislak, C.L., Nakayama, T., and Sun, J.C. (2014). The transcription factor Zbtb32 controls the proliferati

16、ve burst of virus-specific natural killer cells responding to infection. Nat. Immunol. 15, 546553.Nabekura, T., Kanaya, M., Shibuya, A., Fu, G., Gascoigne, N.R., and Lanier, L.L. (2014). Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mous

17、e cytomegalovirus infection. Immunity 40, 225234.Min-Oo, G., Bezman, N.A., Madera, S., Sun, J.C., and Lanier, L.L. (2014). Proapoptotic Bim regulates antigen-specific NK cell contraction and the generation of the memory NK cell pool after cytomegalovirus infection. J. Exp. Med. 211, 12891296.Hunting

18、ton, N.D., Puthalakath, H., Gunn, P., Naik, E., Michalak, E.M., Smyth, M.J., Tabarias, H., Degli-Esposti, M.A., Dewson, G., Willis, S.N., et al. (2007). Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat. Immunol. 8, 856863.Kamimura, Y., and Lanier, L.L. (2015). Homeostati