醫(yī)學(xué)免疫學(xué)課件：巨細(xì)胞病毒（CMV）誘導(dǎo)的自然殺傷（NK）細(xì)胞記憶

1、巨細(xì)胞病毒（CMV）誘導(dǎo)的自然殺傷（NK）細(xì)胞記憶提綱背景NK細(xì)胞NK細(xì)胞記憶的發(fā)現(xiàn)鼠巨細(xì)胞病毒（MCMV）誘導(dǎo)NK細(xì)胞記憶的機制激活與擴增凋亡與生存記憶前體的調(diào)控人巨細(xì)胞病毒（MCMV）誘導(dǎo)NK細(xì)胞記憶展望NK細(xì)胞直接殺傷被病毒感染的自身細(xì)胞或者腫瘤細(xì)胞屬于固有免疫細(xì)胞反應(yīng)快速應(yīng)答模式和強度不因與病原微生物的反復(fù)接觸而改變NK細(xì)胞記憶的發(fā)現(xiàn)半抗原二硝基氟苯 (DNFB)誘發(fā)的接觸性超反應(yīng)(Contact hypersensitivity ,CHS)模型野生型小鼠+DNFBCHS幾周后+DNFB記憶性免疫應(yīng)答無T、B細(xì)胞的小鼠+DNFBCHS幾周后+DNFB記憶性免疫應(yīng)答無T、B、NK細(xì)胞的小

2、鼠+DNFB無CHSDNFB 致敏的小鼠NK細(xì)胞CHSNK細(xì)胞記憶的發(fā)現(xiàn)Ly49H+ NK 細(xì)胞與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細(xì)胞記憶的發(fā)現(xiàn)Ly49H+ NK 細(xì)胞與MCMV記憶NK細(xì)胞的特點：與記憶T細(xì)胞相像二次膨脹（secondary expansion）在體外時有更強的效應(yīng)細(xì)胞功能增強對機體的保護(hù)，對抗病毒特異性缺失糖蛋白m157的MCMV不能引發(fā)這種反應(yīng)MCMV誘導(dǎo)NK細(xì)胞記憶的機制：激活與擴增

4、凋亡與生存記憶前體的調(diào)控MCMV誘導(dǎo)NK細(xì)胞記憶的機制：激活與擴增 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誘導(dǎo)NK細(xì)胞記憶的機制：激活與擴增Signal 1: Ly49H-m157相互作用嵌合小鼠致死劑量輻射小鼠，而后取不同的小鼠骨髓對其進(jìn)行重建野生型骨髓：DAP12缺失型=1：n感染MCMV后Ly49H+ NK 細(xì)胞占大多數(shù)Ly49H+ NK 細(xì)胞初始比例越小，擴增幅度越大Ly49H- NK 細(xì)胞沒有減少感染m157

6、缺失的MCMV后Ly49H+ NK 細(xì)胞比例并沒有特殊變化MCMV誘導(dǎo)NK細(xì)胞記憶的機制：激活與擴增Signal 2: DNAM-1共刺激DNAM-1共刺激分子識別CD155、CD122等胞內(nèi)信號轉(zhuǎn)導(dǎo)區(qū)募集激酶DNAM-1-Fyn通路記憶細(xì)胞生成【必需】效應(yīng)和記憶細(xì)胞擴增【非必需】DNAM-1-PKC通路記憶細(xì)胞生成【必需】效應(yīng)細(xì)胞擴增【必需】通路具體機制不明MCMV誘導(dǎo)NK細(xì)胞記憶的機制：激活與擴增Signal 3: 炎性細(xì)胞因子細(xì)胞因子作用IL-12，轉(zhuǎn)錄因子STAT4NK細(xì)胞的激活，IFN-g生成IFN-gNK細(xì)胞擴增、分化（非自分泌途徑）IL-33，IL-18，MyD88調(diào)控特異性NK

7、細(xì)胞的擴增IL-12，IL-18，type I IFNs增殖、保護(hù)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誘導(dǎo)NK細(xì)胞記憶的機制：凋亡與生存效應(yīng)NK細(xì)胞凋亡下調(diào)促活分子Bcl-2上調(diào)Bim介導(dǎo)的促凋亡信號IL-15的作用保持過繼轉(zhuǎn)入的效應(yīng)、記憶NK細(xì)胞數(shù)量抑制細(xì)胞凋亡線粒體的作用累積破損的線粒體

8、開始Bim介導(dǎo)的細(xì)胞凋亡記憶細(xì)胞通過自噬移除破損線粒體線粒體自噬受體BNIP3和BNIP3L效應(yīng)T細(xì)胞如何存活機制不明MCMV誘導(dǎo)NK細(xì)胞記憶的機制：凋亡與生存IL-15的作用機制IL-15激活PI(3)kAkt磷酸化Foxo3a防止Bim轉(zhuǎn)錄上調(diào)激活Erk1/2Bim磷酸化的Bim被蛋白酶體降解限制Bim水平促表達(dá)Mcl-1Noxa拮抗拮抗Bcl-2相關(guān)蛋白A1microRNA-155抑制拮抗SOCS1激活MCMV誘導(dǎo)NK細(xì)胞記憶的機制：凋亡與生存效應(yīng)NK細(xì)胞凋亡下調(diào)促活分子Bcl-2上調(diào)Bim介導(dǎo)的促凋亡信號IL-15的作用保持過繼轉(zhuǎn)入的效應(yīng)、記憶NK細(xì)胞數(shù)量抑制細(xì)胞凋亡線粒體的作用累積破

9、損的線粒體開始Bim介導(dǎo)的細(xì)胞凋亡記憶細(xì)胞通過自噬移除破損線粒體線粒體自噬受體BNIP3和BNIP3LMCMV誘導(dǎo)NK細(xì)胞記憶的機制：記憶前體的調(diào)控外在環(huán)境因素KLRG1+ NK細(xì)胞與KLRG1- NK細(xì)胞KLRG1- NK細(xì)胞分裂能力更強，優(yōu)先產(chǎn)生記憶細(xì)胞IL-15的作用機制細(xì)胞固有因素生成過程中RAG表達(dá)表面KLRG1少優(yōu)先產(chǎn)生記憶細(xì)胞生成過程中RAG不表達(dá)表面KLRG1多高反應(yīng)性，難存活不清楚產(chǎn)生記憶NK細(xì)胞的效應(yīng)細(xì)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誘導(dǎo)NK細(xì)胞記憶的機制：記憶前體的調(diào)控外在環(huán)境因素KLRG1+ NK細(xì)胞與KLRG1- NK細(xì)胞KLRG1- NK細(xì)胞分裂能力更強，優(yōu)先產(chǎn)生記憶細(xì)胞IL-15的作用機制細(xì)胞固有因素生成過程中RAG表達(dá)表面KLRG1少優(yōu)先產(chǎn)生記憶細(xì)胞生成過程中RAG不表達(dá)表面KLRG1多高反應(yīng)性，難存活不清楚產(chǎn)生記憶NK細(xì)胞的效應(yīng)細(xì)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誘導(dǎo)NK細(xì)胞記憶NKG2C+NK細(xì)胞可能是NK細(xì)胞發(fā)揮記憶功能的主力激活、增殖信號HLA-EIL-12NKG2CCD57可以對某些病毒做出反應(yīng)HBV、HCV、HIV可能受某些病毒影響孩童青少年、成年受體多樣性改變？小結(jié)與展望許多作用機制尚不了解效應(yīng)NK細(xì)胞是否像CD8

13、+T細(xì)胞一樣有專門產(chǎn)生記憶細(xì)胞的？產(chǎn)生記憶細(xì)胞具體過程是怎樣的？怎樣將這些研究應(yīng)用于臨床？幫助獲得性免疫功能不強的人對抗CMV？找到方法廣泛提高人群免疫力？對于其他病原體NK細(xì)胞是否有類似機制？其他固有免疫細(xì)胞是否也有類似特性？參考文獻(xiàn)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