學(xué)習(xí)獲得性細(xì)胞免疫應(yīng)答

1、學(xué)習(xí)獲得性細(xì)胞免疫應(yīng)答Peripheral lymphoid organs and immune recognition(外周淋巴器官與免疫識別)啟動階段 Ag processing and presentation T cell stimulation - activation增殖 T cell activation and proliferation效應(yīng)階段Effector T cells調(diào)節(jié)復(fù)原Immunoregulation9-1 獲得性免疫應(yīng)答的基本過程9-2 DC啟動獲得 性免疫應(yīng)答被膜輸出淋巴管外 來 抗 原 的 捕 獲 與 遞 呈 局 部 組 織引流淋巴管樹突細(xì)胞異物抗原輸入淋

2、巴管皮質(zhì)淋 巴 結(jié)9-3 T 細(xì)胞的活化 9-3-1 T-APC InteractionCD4MHC-IITCR/CD31ICAM-1B7-1B7-2LFA-1LFA-1ICAM-3LFA-3B7-1CD28CD28LFA-1ICAM-3CD22參與 T 細(xì)胞活化的膜表面分子T細(xì)胞APCCTLA-4T細(xì)胞與APC的附著TCR掃描APC表面9-3-2 ecognition of MHC/peptide complex by TCR TCR 識別 MHC/抗原肽復(fù)合分子 TCR抗原肽MHCT 細(xì)胞抗原遞呈細(xì)胞TCR抗原結(jié)合部位抗原的特異性識別TCR 識別 MHC/抗原肽 的分子解剖MHC-a 螺旋

3、抗原肽CDR1CDR2CDR3CDR3CDR2CDR1TCR-b 鏈TCR-a 鏈MHC-a 螺旋APC Th細(xì)胞活性封閉Th細(xì)胞活化的雙信號模型IL-2RAPCTh信號1信號2炎癥 LPS 細(xì)菌 化學(xué)趨化因子 補體 TNF-a IL-1 IL-6IL-2Th信號1Th細(xì)胞活化、增殖9-3-3 T細(xì)胞活化的“雙信號模型”Ag Recognition Provides the First Signal for T cell Activation 活性封閉Tc 細(xì)胞活化的雙信號模型IL-2APC 1 活化，擴增ThTcAPC 2TcfynPLCCa+ZAP-70激酶鏈的信號整合轉(zhuǎn)錄因子被活化早期基

4、因 IL-2基因 IL-2Ra基因T 細(xì)胞活化的信號轉(zhuǎn)導(dǎo)CD4TCRLCK PI-3kT細(xì)胞活化過程中的信號轉(zhuǎn)導(dǎo)9-4 抗原特異性淋巴細(xì)胞的克隆擴增與選擇0 3 5 8 15 20 30 40 50 100 200 300 400 10107610105431010240CTL病毒CTL(%)6080209-5 Effector T Cells (效應(yīng)T細(xì)胞)輔助性T細(xì)胞：Th1與Th2Tc細(xì)胞效應(yīng)T細(xì)胞的調(diào)節(jié)再次免疫應(yīng)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 殺傷靶細(xì)胞的機制9-6 效應(yīng)T細(xì)胞的MHC限制性Rolf ZinkernaglePeter DohertyNobel Prize 1996 Ag Specificity9-7 Adhesion molecules and Immigration of lymphocytes 脾 臟（5小時）血液循環(huán)（30分鐘）骨髓、上皮腹腔 淋

6、巴結(jié)（12小時）粘摸下組織其它組織肝 、大腦輸出淋 巴管 輸 入 淋 巴 管45%42%10%活化淋巴細(xì)胞未活化淋巴細(xì)胞不參加再循環(huán)的細(xì)胞 （ ？）10%52% 淋 巴 細(xì) 胞 循 環(huán) 途 徑免 疫 后 天 數(shù)外周血中抗原特異性T細(xì)胞的比率感應(yīng)階段初次免疫再次免疫1/100001/10001/1000 7 14 21 28 35 42 T 細(xì) 胞 免 疫 應(yīng) 答 的 一 般 規(guī) 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 獲得性免疫應(yīng)答的調(diào)節(jié)神經(jīng)內(nèi)分泌系統(tǒng)對免疫系統(tǒng)的調(diào)節(jié)作用抗原對免疫應(yīng)答的調(diào)節(jié)作用活化誘導(dǎo)的細(xì)胞死亡（CTLA4）調(diào)節(jié)性 T 細(xì)胞轉(zhuǎn)導(dǎo)負(fù)性信號的免疫細(xì)胞膜分子中樞神經(jīng)系統(tǒng)松果體激素精神因素神經(jīng)肽免疫介質(zhì)內(nèi)分泌激素內(nèi)分泌系統(tǒng)免疫系統(tǒng)免疫介質(zhì)內(nèi)分泌激素神 經(jīng) 內(nèi) 分 泌 與 免 疫 系 統(tǒng) 的 相 互 調(diào) 節(jié)CTLA-4CD28PPPB7-2B7-1APC凋亡信號活化信號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