学习获得性细胞免疫应答

1、学习获得性细胞免疫应答Peripheral lymphoid organs and immune recognition(外周淋巴器官与免疫识别)启动阶段 Ag processing and presentation T cell stimulation - activation增殖 T cell activation and proliferation效应阶段Effector T cells调节复原Immunoregulation9-1 获得性免疫应答的基本过程9-2 DC启动获得 性免疫应答被膜输出淋巴管外 来 抗 原 的 捕 获 与 递 呈 局 部 组 织引流淋巴管树突细胞异物抗原输入淋

2、巴管皮质淋 巴 结9-3 T 细胞的活化 9-3-1 T-APC InteractionCD4MHC-IITCR/CD31ICAM-1B7-1B7-2LFA-1LFA-1ICAM-3LFA-3B7-1CD28CD28LFA-1ICAM-3CD22参与 T 细胞活化的膜表面分子T细胞APCCTLA-4T细胞与APC的附着TCR扫描APC表面9-3-2 ecognition of MHC/peptide complex by TCR TCR 识别 MHC/抗原肽复合分子 TCR抗原肽MHCT 细胞抗原递呈细胞TCR抗原结合部位抗原的特异性识别TCR 识别 MHC/抗原肽 的分子解剖MHC-a 螺旋

3、抗原肽CDR1CDR2CDR3CDR3CDR2CDR1TCR-b 链TCR-a 链MHC-a 螺旋APC Th细胞活性封闭Th细胞活化的双信号模型IL-2RAPCTh信号1信号2炎症 LPS 细菌 化学趋化因子 补体 TNF-a IL-1 IL-6IL-2Th信号1Th细胞活化、增殖9-3-3 T细胞活化的“双信号模型”Ag Recognition Provides the First Signal for T cell Activation 活性封闭Tc 细胞活化的双信号模型IL-2APC 1 活化，扩增ThTcAPC 2TcfynPLCCa+ZAP-70激酶链的信号整合转录因子被活化早期基

4、因 IL-2基因 IL-2Ra基因T 细胞活化的信号转导CD4TCRLCK PI-3kT细胞活化过程中的信号转导9-4 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 10107610105431010240CTL病毒CTL(%)6080209-5 Effector T Cells (效应T细胞)辅助性T细胞：Th1与Th2Tc细胞效应T细胞的调节再次免疫应答TTcTh0Tc2Tc1TregTh?Th2Th1TregCD4+CD8+CD4+25+ 2 hrs Wash x 3 1 hrs Wash x 3 51Cr 4 hrs 3

5、7BCLMeasure Specific 51Cr-Release+ VirusExperimental procedure for testing antigen-specific CTL activityT cells Harvest supernatantCTL 杀伤靶细胞的机制9-6 效应T细胞的MHC限制性Rolf ZinkernaglePeter DohertyNobel Prize 1996 Ag Specificity9-7 Adhesion molecules and Immigration of lymphocytes 脾 脏（5小时）血液循环（30分钟）骨髓、上皮腹腔 淋

6、巴结（12小时）粘摸下组织其它组织肝 、大脑输出淋 巴管 输 入 淋 巴 管45%42%10%活化淋巴细胞未活化淋巴细胞不参加再循环的细胞 （ ？）10%52% 淋 巴 细 胞 循 环 途 径免 疫 后 天 数外周血中抗原特异性T细胞的比率感应阶段初次免疫再次免疫1/100001/10001/1000 7 14 21 28 35 42 T 细 胞 免 疫 应 答 的 一 般 规 律9-8 Immunological memoryMemory T Cells:Resting stateLong lived (continuously renewal)Easily triggered (do no

7、t need co-stimulatory molecules)Responsible for maintaining immunological memory 9-8 获得性免疫应答的调节神经内分泌系统对免疫系统的调节作用抗原对免疫应答的调节作用活化诱导的细胞死亡（CTLA4）调节性 T 细胞转导负性信号的免疫细胞膜分子中枢神经系统松果体激素精神因素神经肽免疫介质内分泌激素内分泌系统免疫系统免疫介质内分泌激素神 经 内 分 泌 与 免 疫 系 统 的 相 互 调 节CTLA-4CD28PPPB7-2B7-1APC凋亡信号活化信号CD4+CD25+ Regulatory T cellsA un

8、ique lineage of regulatory T cells capable of maintaining self tolerance in vivoTCD8CD4CD4+25+Th1Tc2Tc1Th2Th3Tr1Peripheral T lymphocyte5-10%30%Th4?60%ThymusCD4EffectorsRegulatorsNormal mouseCD4+T-cell suspensions eliminated of CD25+ cells T cell-deficient mouseAutoimmune diseases thyroid stomach sal

9、ivary gland Langerhans islets adrenal glands ovaries testes CD4+CD25+ Tr cells: Comprise 5-10% of peripheral CD4 T cells in human and miceProduced in thymus as an unique lineage of CD4 T cellsSecret IL-10 and/or TGF-b, but little IL-2Anergic and suppressive CD45RBlow, CTLA-4 highMaintain immunologic

10、al toleranceInhibit proliferation of CD4+CD25- T cells in vitro, need activation via TCR and cell-cell contact to function, but IL-10 and TGF-b may also participateSuppressive capacity could be reversed by adding exogenous IL-2, by using anti-CD28 mAb Function of CD4+CD25+ T cellsAnti-idiotypic networkSurface molecules transducing inhibitory or apoptosis signals Regulatory T cells Ts cells Anti-idiotypic T cells Th1, Th2, Th3, Tr1 CD4+25+ CD4+ T cells are the main targets of