T淋巴细胞介导的细胞免疫应答.ppt

,第十二章 T淋巴细胞介导的细胞免疫应答,免疫学教研室,目标,免疫应答 （immune response）,概念 免疫细胞识别抗原后活化、增殖、分化为效应细胞，并通过其所分泌的抗体或细胞因子表现出一定生物学效应的过程。,适应性免疫应答的基本原理,类型,1,2,3,4,5,适应性免疫应答的基本过程,局 部 组 织,引流淋巴管,树突细胞,异物抗原,APC启动适应性免疫应答,外来抗原的捕获与递呈,TC,TCR,MHC-I,Th1,TCR,MHC-II,Cellular immunity,CTL: Cytotoxic T Lymphocyte,(1)T细胞与APC的黏附,(2) TCR扫描APC表面,(3) T细胞通过TCR对抗原肽进行识别,ab TCR,ab TCR,CD 8,抗原肽,HLA- I,抗原肽,HLA- II,TCR Co-receptor - CD4 和 CD8,TCR 立体结构 -,Diversity and Specificity,TCR 识别 MHC/抗原肽 的分子解剖,MHC-a 螺旋,抗原肽,CDR1,CDR2,CDR3,CDR3,CDR2,CDR1,TCR-b 链,TCR-a 链,MHC-a 螺旋,40 30 20 10 0,10 20 30 40 50 60 70 80 90 100 110,TCR Va 区氨基酸序列,氨基酸残基的变异百分率,TCR 的 多 样 性,CDR1,CDR2,CDR3,ab-TCR 的多样性与抗原特异性,-S-S-,Va,Ca,Vb,Cb,g,e,d,-S-S-,TCR-ab,CD3 复合体,z,h,z,z,-S-S-,TCR-CD3 复 合 分 子,e,胞膜,胞浆,ITAM,糖基,TCR-CD3复合分子,ITAM:Immunoreceptor tyrosine-based activation motifs,APC,Th细胞活性封闭,Th细胞活化的双信号模型,IL-2R,APC,Th,信号1,信号2,炎症 LPS 细菌,化学趋化因子 补体 TNF-a IL-1 IL-6,IL-2,Th,信号1,Th细胞活化、增殖,(4) T细胞活化的“双信号模型”,A 活化,*,免疫突触 immunological synapse,fyn,PLC,Ca+,ZAP-70,激酶链的信号整合,转录因子被活化,早期基因,IL-2基因,IL-2Ra基因,T 细胞活化的信号转导,CD4,TCR,LCK,PI-3k,Activation,Anergy,抗原特异性淋巴细胞的克隆扩增与选择,0 3 5 8 15 20 30 40 50 100 200 300 400,10 10,7,6,10 10,5,4,3,10 10,2,40,CTL,病毒,CTL(%),60,80,20,IL-2 and IL-2R for T cells,T,Th2,Th?,Tc1,Tc2,Treg,Th0,CD4+,Tc,CD8+,Treg,CD4+25+,Effector T Cells (效应T细胞),辅助性T细胞：,Tc细胞：直接杀伤靶细胞,Th1,Th2,细胞免疫,体液免疫,分泌细胞因子,Th,CD4+,Tc,CD8+,CD4+,(1) 辅助性T细胞：,活化,分泌细胞因子,a. 效应性Th1细胞,IL-2：促进T细胞增殖 IFN-：活化M增强其表达MHC-II分子的表达 TNF-：使血管内皮细胞表达粘附因子，分泌 趋化因子,细胞免疫，炎症反应（胞内感染），迟发性变态反应（DHT）,活化,b. 效应性Th2细胞,抗体生成类别转换,B细胞增殖、抗体生成,2. 杀伤性T细胞 CTL,CTL,CTL细胞活化的双信号模型,活性封闭,APC 1,CTL,IL-2,活化 扩增,Th,CTL,APC 2,*,图 CTL介导的靶细胞杀伤过程,靶细胞,颗粒,CTL,CD8 TCR,MHC I-肽,CTL细胞,器重排,CTL颗粒,外吐,膜损伤,偶合物,形成,CTL再循环,效应阶段,Flash lymphocyte development induction of apoptosis,FADD:FAS相关的含死亡区域的蛋白,Caspase-8:胱冬肽酶8,CAD: Caspase activated DNase,Phagocytes with ingested microbes; microbial antigens in vesicles,Infected cell with microbes in cytoplasm,CD4+ effector T cells (TH1 cells),CD8+ T cells (CTL),CD8+ T cells (CTL),Macrophage activation: killing of ingested macirobes,Inflammation,Killing of infected cells,Types of T cell-mediated immune reactions,CD8+ T cells (CTL),CD4+ effector T cells (TH1 cells),CD4+ T cells,CD8+ T cells,Antigen recognition in lymphoid orgens,T cell expansion and differentiation,Differentiated effector T cells enter circulation,Effector T cell encounter antigens in peripheral tissues,Migration of effector T cells and other leukocytes to site of antigen,Differentiated effector T cells enter circulation,Effector T cell encounter antigens in peripheral tissues,Effector functions of T cells,Macrophage activation: killing of phagocytosed microbes,CTL killing of target cell,Activation of effector T cells,The induction and effector phases of cell-mediated immunity,naive CD4+ T cells,APC,Microbes,Proliferation and differentiation,IFN-,IFN-,LT,TNF,B cell,TH1 cells,Fc receptor,Macrophage activation (enhanced microbial killing ),Complement-binding and opsonizing antibodies,Opsonization and phagocytosis,Neutrophil activation (enhanced microbial killing),Effector functions of TH1 cells,naive CD4+ T cells,APC,Microbes,Proliferation and differentiation,B cell,TH2cells,Eosinophil,Mast cell degranulation,Activated macrophage,Suppression of macrophage activation,Eosinophil activation,Helminth (蠕虫),Production of IgE,Production of neutralizing IgG antibodies,IL-10, IL-4,IL-4,IL-5,Effector functions of TH2 cells,Tc,NK,CTL,与,NK,细胞的比较,MHC/抗原肽提供杀伤信号,MHC分子提供杀伤抑制信号,病毒感染后期清除被病毒感染的细胞,病毒感染初期防止病毒扩散,Rolf Zinkernagle Peter Doherty Nobel Prize 1996,You won the Nobel Prize in Medicine in 1996, for discovering how killer T-cells recognize infecte