醫(yī)學(xué)免疫學(xué)教學(xué)匯編-9細(xì)胞應(yīng)答

薛殷彤副教授北京大學(xué)醫(yī)學(xué)部免疫系Tel/Faxmail:maybegood@精選課件1991,Dept.BasicMedicine,BMU,BM1999,MTC,KarolinskaInstitute,Ph.D2000,HSC,BU,AssociateProf.精選課件PUBLICATIONS

1.XueY.Castanos-VelezE.BiberfeldP.JondalM.Anti-CD3inducedthymocyteapoptosisinvivorequiretheantibodyFcdomain.ScandinavianJournalofImmunology.51(5):441-6,2000May.20253458Abstract|CompleteReference2.PazirandehA.XueY.RafterI.SjovallJ.JondalM.OkretS.Paracrineglucocorticoidactivityproducedbymousethymicepithelialcells.FASEBJournal.13(8):893-901,1999May.99242554Abstract|CompleteReference3.XueY.ChomezP.Castanos-VelezE.BiberfeldP.PerlmannT.JondalM.PositiveandnegativethymicselectioninTcellreceptor-transgenicmicecorrelatewithNur77mRNAexpression[publishederratumappearsinEurJImmunol1997Oct;27(10):2748].EuropeanJournalofImmunology.27(8):2048-56,1997Aug.97439488Abstract|CompleteReference4．A.Pazirandeh,Y.Xue,T.Prestegaard,M.JondalandS.Okret.EffectsofalteredglucocorticoidsensitivityintheTcelllineageonthymocyteandTcellhomeostasis.FASEBJournal.Inpress(10.1096FJE01-0891COM)5.ZhangJ.XueY.JondalM.SjovallJ.7alpha-Hydroxylationand3-dehydrogenationabolishtheabilityof25-hydroxycholesteroland27-hydroxycholesteroltoinduceapoptosisinthymocytes.EuropeanJournalofBiochemistry.247(1):129-35,1997Jul1.97390079Abstract|CompleteReference6.XueY.MurdjevaM.OkretS.McConkeyD.KiuossisD.JondalM.InhibitionofI-Ad-,butnotDb-restrictedpeptide-inducedthymicapoptosisbyglucocorticoidreceptorantagonistRU486inTcellreceptortransgenicmice.EuropeanJournalofImmunology.26(2):428-34,1996Feb.96206149Abstract|CompleteReference7.JondalM.XueY.McConkeyDJ.OkretS.ThymocyteapoptosisbyglucocorticoidsandcAMP.[Review][89refs]CurrentTopicsinMicrobiology&Immunology.200:67-79,1995.95361542CompleteReference8.PazirandehA.XueY.OkretS.JondalM.GlucocorticoidresistanceinthymocytesfrommiceexpressingaTcellreceptortransgene.Biochemical&BiophysicalResearchCommunications.276(1):189-96,2000Sep16.20462938精選課件精選課件卡洛林斯卡醫(yī)學(xué)研究所(KAROLINSKAINSTITUTE)和諾貝爾獎(jiǎng)(NOBELPRIZE)精選課件細(xì)胞免疫應(yīng)答(CellularImmuneResponses)精選課件免疫應(yīng)答(immuneresponse)免疫細(xì)胞因?qū)乖奶禺愖R(shí)別而活化,增殖,分化,最終形成效應(yīng)細(xì)胞,并通過其所分泌的抗體或者細(xì)胞因子表現(xiàn)出一定生物學(xué)效應(yīng)的過程.精選課件啟動(dòng)階段

Mf清除(固有免疫)AgDC/Mf

淋巴結(jié)(誘導(dǎo)特異性T&B)增殖

activationandproliferationAg特異性T/B的克隆選擇和擴(kuò)增效應(yīng)階段調(diào)節(jié)復(fù)原

Immunoregulation免疫應(yīng)答的基本過程精選課件獲得性免疫應(yīng)答的啟動(dòng)DC(resting)DC活化淋巴結(jié)(DC:MHC-II/B7)

Ag/TNF-aAgprocessing&presentationTNF-a2.RestingMf(MHC/B7

)ActivatedMfDCactivatingLPS,IFN-gAgprocessing&presentation3.SolubleAg,皮下／內(nèi)皮（調(diào)理素）淋巴結(jié)(DC/Mf)血液中脾(Mf)精選課件DC啟動(dòng)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)胞異物抗原輸入淋巴管皮質(zhì)淋巴結(jié)精選課件蛋白質(zhì)抗原的處理與遞呈內(nèi)源性抗原遞呈途徑(I類抗原）外源性抗原遞呈途徑（II類抗原）*是細(xì)胞內(nèi)或細(xì)胞外合成的抗原肽精選課件TAPMHC－I分子的合成MHC－I，?2m和抗原肽的組裝運(yùn)輸至膜表面短肽內(nèi)源性蛋白

細(xì)胞核CD8T細(xì)胞APCB7CD281234

MHC-I類分子抗原呈遞途徑MHC-ICD8TCR抗原肽蛋白酶體精選課件內(nèi)源性抗原遞呈途徑

細(xì)胞內(nèi)合成的蛋白質(zhì)抗原在胞漿內(nèi)被蛋白酶體裂解為小的肽段，通過TAP轉(zhuǎn)運(yùn)至內(nèi)質(zhì)網(wǎng)中。在此具有一定基序的肽段與MHC-Ia和b2m結(jié)合并通過高爾基體被遞呈于細(xì)胞表面。CD8+的T細(xì)胞通過其TCR和CD8分子識(shí)別MHC-I/抗原肽復(fù)合分子。精選課件MHC-I抗原抗原遞呈途徑（classIantigenpresentationpathway）精選課件自身蛋白（功能/結(jié)構(gòu)）降解成單個(gè)氨基酸

TAP合成微生物蛋白內(nèi)質(zhì)網(wǎng)（+MHC-I）高爾基體（I類）細(xì)胞表面精選課件

細(xì)胞核CD4T細(xì)胞APCB7CD285

MHC-II類分子抗原呈遞途徑MHC-II分子的合成a,b鏈和不變鏈的運(yùn)輸運(yùn)輸至膜表432溶酶體吞噬體CD4TCR抗原肽1精選課件外源性遞呈途徑

細(xì)胞內(nèi)質(zhì)網(wǎng)中合成的MHC-IIa和b鏈與不變鏈?zhǔn)紫冉M裝?？乖f呈細(xì)胞（APC）獲取外源性抗原之后形成吞噬體，隨后與溶酶體融合為吞噬溶酶體，溶酶體酶在此將外來抗原裂解為肽段。隨后吞噬溶酶體與含有MHC-II分子的內(nèi)體融合，具有適當(dāng)基序的肽段得以與MHC-II分子結(jié)合，并與之一起表達(dá)于細(xì)胞表面⑤。CD4+的T細(xì)胞通過其TCR和CD4分子識(shí)別MHC-II/抗原肽復(fù)合分子。精選課件MHC-II抗原遞呈途徑（classIIantigenpresentationpathway）*CLIP,classII-associatedinvariantchainpeptide精選課件外源性抗原吞噬體溶酶體吞噬溶酶體MHC-II+恒定鏈（內(nèi)質(zhì)網(wǎng)中）MHC-II+CLIP（胞內(nèi)小體）MHC-II，-CLIP，+肽細(xì)胞表面融合融合（II類）精選課件T細(xì)胞的活化（Ｔ細(xì)胞對(duì)Ag的識(shí)別）１．T-APC的黏附２．TCR–MHC/Peptide的識(shí)別３．共刺激因子，第二信號(hào)４．信號(hào)傳導(dǎo)（轉(zhuǎn)導(dǎo)）５．特異性Ｔ細(xì)胞的活化，增殖和分化精選課件T-APC的黏附*T細(xì)胞表面有多種黏附分子(adhesionmolecules)*黏附分子有整合素家族和Ig超家族的一些成員*維持T/APC短暫的相對(duì)穩(wěn)定結(jié)合精選課件CD4MHC-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-4—T細(xì)胞與APC的附著精選課件TCR–MHC/Peptide的識(shí)別*MHC限制*TCR輔助受體的限制(CD4-MHC-II/b2,CD8-MHC-I/a3)，即其與MHC的結(jié)合是Ｔ細(xì)胞活化的必要條件精選課件精選課件精選課件共刺激分子，第二信號(hào)*APC的共刺激分子(co-stimulatorymolecules)與Ｔ細(xì)胞表面的配體的結(jié)合為Ｔ細(xì)胞的活化提供了第二信號(hào)*TCR-MHC/Peptide為第一信號(hào)*Thcell,B7.1/B7.2(CD80/CD86)----CD28Tccell,B7/IL-2-------CD28/IL-2R精選課件精選課件APC

Th細(xì)胞活性封閉Th細(xì)胞活化的雙信號(hào)模型IL-2RAPCTh信號(hào)1信號(hào)2炎癥LPS細(xì)菌化學(xué)趨化因子補(bǔ)體TNF-aIL-1IL-6IL-2Th信號(hào)1Th細(xì)胞活化、增殖精選課件

活性封閉Tc

細(xì)胞活化的雙信號(hào)模型IL-2APC1

活化，擴(kuò)增ThTcAPC2Tc精選課件信號(hào)傳導(dǎo)（轉(zhuǎn)導(dǎo)）(Signaltransduction)*TCR與MHC/P結(jié)合導(dǎo)致CD45分子構(gòu)象變化并靠攏CD4/CD8.*CD45的胞漿區(qū)具有磷酸酯酶活性，使CD4/CD8胞區(qū)結(jié)合的酪氨酸激酶(PTK)lck,去磷酸化而激活*激活的lck使CD3胞內(nèi)區(qū)的ITAM(免疫受體酪氨酸活化基序)磷酸化，使之與fyn和ZAP-70等蛋白激酶結(jié)合．*fyn和ZAP-70通過激活磷酸脂酶C(PLC)造成胞漿內(nèi)鈣離子濃度驟升和DNA轉(zhuǎn)錄因子的活化．*CD28胞內(nèi)區(qū)結(jié)合的酯醇三磷酸激酶(PI-3k)漿內(nèi)激酶級(jí)聯(lián)反應(yīng)激活相應(yīng)的DNA轉(zhuǎn)錄因子*激活的DNA轉(zhuǎn)錄因子進(jìn)入胞核，啟動(dòng)細(xì)胞增殖早期基因和IL-2基因/IL-2Ra基因的表達(dá)精選課件CD28PI-3k激酶鏈的信號(hào)整合轉(zhuǎn)錄因子被活化胞核早期基因IL-2基因/IL-2Ra基因精選課件細(xì)胞免疫應(yīng)答的效應(yīng)*黏附分子使效應(yīng)細(xì)胞與靶細(xì)胞接觸*識(shí)別MHC/Peptide*釋放細(xì)胞因子或殺傷靶細(xì)胞精選課件精選課件輔助性Ｔ細(xì)胞(Hel