《抗原的加工与呈递》PPT课件.ppt

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1、第第1111章章 抗原的加工与递呈抗原的加工与递呈Antigen Processing&PresentationT cells do not recognise native antigensT cells do not recognise native antigensYYBYYYYYYYBYTYTProliferation and antibody productionNo proliferationNo cytokine releaseCross-linking of surface membrane IgYBYBYBYBYBYBYBCell surfacepeptidesof AgAn

2、tigens must be processed in orderAntigens must be processed in orderto be recognised by T cellsto be recognised by T cellsYT T cellresponseNo T cellresponseNo T cellresponseNo T cellresponseNo T cellresponseSolublenative AgCell surfacenative AgSoluble peptidesof AgCell surface peptides of Ag present

3、ed by cells that express MHC antigensANTIGENPROCESSINGYTMHC directs the response of T cells toMHC directs the response of T cells toforeign antigensforeign antigensYTAgYTAgAnti responseNo anti responseMHC antigens PRESENT foreign antigens to T cellsCells that present antigen are ANTIGEN PRESENTING C

4、ELLSYTYTYTYTYBlockinganti-MHCantibodyYYYAgAgB B细胞细胞浆细胞浆细胞AbAbAPCAPCThTh细胞细胞AgAg肽肽-MHC-MHC分子分子T T细胞细胞TcTc细胞细胞ContentsContents 抗原递呈细胞抗原递呈细胞抗原加工递呈途径抗原加工递呈途径第一节第一节 抗原递呈细胞抗原递呈细胞Antigen Presenting CellsAntigen Presenting Cells 基本概念基本概念 抗原递呈细胞抗原递呈细胞一、基本概念一、基本概念抗原加工与递呈抗原加工与递呈（Antigen processing and presenta

5、tionAntigen processing and presentation）抗原加工是指蛋白质抗原在细胞内被降解成能与抗原加工是指蛋白质抗原在细胞内被降解成能与MHCMHC结合的肽的过程。结合的肽的过程。抗原递呈是指抗原递呈是指MHCMHC分子与抗原肽结合，将其展示分子与抗原肽结合，将其展示于细胞表面供于细胞表面供T T细胞识别的过程。细胞识别的过程。Influenza virus内源性抗原内源性抗原（endogenous antigensendogenous antigens）指细胞内产生的蛋白质抗原指细胞内产生的蛋白质抗原细胞产生的自身固有蛋白质细胞产生的自身固有蛋白质胞内寄生病毒或其

6、它病原体产生的蛋白质胞内寄生病毒或其它病原体产生的蛋白质细胞恶性转化后产生的突变蛋白，即肿瘤抗原细胞恶性转化后产生的突变蛋白，即肿瘤抗原有核细胞内加工，由有核细胞内加工，由MHCMHC分子递呈分子递呈MMMMListeria外源性抗原外源性抗原(exogenous antigens)(exogenous antigens)指由细胞外进入细胞的蛋白质抗原指由细胞外进入细胞的蛋白质抗原细胞摄入的各种病原体和疫苗细胞摄入的各种病原体和疫苗在吞噬体和内体中生长的病原体在吞噬体和内体中生长的病原体摄入的自身蛋白摄入的自身蛋白抗原递呈细胞内加工，由抗原递呈细胞内加工，由MHCMHC分子递呈分子递呈二、二、

7、抗原递呈细胞抗原递呈细胞抗原递呈细胞抗原递呈细胞 (antigen presenting cell(antigen presenting cell，APC)APC)能够摄取、加工、处理抗原并将能够摄取、加工、处理抗原并将AgAg信息信息递呈给抗原特异性淋巴细胞（递呈给抗原特异性淋巴细胞（T T细胞）细胞）的一类免疫细胞。包括巨噬细胞、树突的一类免疫细胞。包括巨噬细胞、树突状细胞、成熟状细胞、成熟B B细胞等细胞等广义广义APCAPC所有有核细胞所有有核细胞表达表达MHCMHC类分子类分子专职专职APCAPC(professional(professional APC)APC)MM，DCDC，B

8、 B细胞等细胞等表达表达MHCMHC类分子类分子兼职兼职APCAPC(non(non-professional APC)-professional APC)内皮细胞，上皮细胞，激活的内皮细胞，上皮细胞，激活的T T细胞等细胞等某些因素刺激后表达某些因素刺激后表达MHC-MHC-类分子类分子1、树突状细胞、树突状细胞（dendritic cell,DC）典型树突状形态典型树突状形态功能最强的功能最强的APCAPCDCDC分类分类根据起源根据起源淋巴系淋巴系DCDC滤泡滤泡DC(FDC)DC(FDC)髓系髓系DCDC（CD11cCD11c+）郎格汉斯细胞郎格汉斯细胞 (LC)(LC)并指状并指状D

9、C(IDC)DC(IDC)并指状树突细胞并指状树突细胞滤泡状滤泡状树突细胞树突细胞B细胞细胞未成熟未成熟DCDC和成熟和成熟DCDC未成熟未成熟DC(ImmatureDC(Immature DC)DC)皮肤、胃肠道、呼吸道等上皮内及实质器官间质内皮肤、胃肠道、呼吸道等上皮内及实质器官间质内摄取抗原摄取抗原并迁移至引流淋巴器官并迁移至引流淋巴器官胞饮（吞饮）胞饮（吞饮）受体介导内吞受体介导内吞吞噬弱吞噬弱表达低水平的表达低水平的MHCMHC分子、协同刺激分子和粘附分子分子、协同刺激分子和粘附分子成熟过程中的重要变化成熟过程中的重要变化:表达趋化因子受体，获得向引流淋巴结表达趋化因子受体，获得向引

10、流淋巴结迁移的能力迁移的能力加工递呈抗原加工递呈抗原，表达大量肽，表达大量肽-MHC-MHC复合物复合物协同刺激分子和粘附分子表达上调协同刺激分子和粘附分子表达上调成熟成熟DC(MatureDC(Mature DC)DC)淋巴结，脾及派氏集合淋巴管淋巴结，脾及派氏集合淋巴管高表达高表达MHCMHC分子、协同刺激分子及粘附分子分子、协同刺激分子及粘附分子很强的抗原递呈能力很强的抗原递呈能力上皮组织中的上皮组织中的LCLC捕捉外来抗原后即进入引流淋巴结的捕捉外来抗原后即进入引流淋巴结的T T细胞区，成为细胞区，成为IDCIDC2 2、巨噬细胞、巨噬细胞(Macrophage,M)来源、分布来源、分

11、布前单核细胞（骨髓）前单核细胞（骨髓）单核细胞（血液）单核细胞（血液）巨噬细胞（组织器官）巨噬细胞（组织器官）单核细胞体积较大，蹄状核（左，普通光镜）单核细胞体积较大，蹄状核（左，普通光镜）透射电镜显示其高尔基体发达、线粒体丰富、胞浆透射电镜显示其高尔基体发达、线粒体丰富、胞浆颗粒明显（中）颗粒明显（中）扫描电镜显示腹腔巨噬细胞粘附于玻璃表面（右）扫描电镜显示腹腔巨噬细胞粘附于玻璃表面（右）单 核 巨 噬 细 胞功能功能吞噬消灭病原体吞噬消灭病原体加工递呈抗原，激发特异性免疫应答加工递呈抗原，激发特异性免疫应答免疫应答的效应细胞免疫应答的效应细胞MM摄取抗原途径摄取抗原途径胞吞作用胞吞作用吞噬

12、吞噬吞饮吞饮受体介导内吞受体介导内吞模式识别受体模式识别受体（pattern recognition receptorspattern recognition receptors，PRRPRR）3 3、B B细胞细胞B B细胞摄取抗原途径细胞摄取抗原途径加工递呈可溶性抗原加工递呈可溶性抗原BCRBCR介导内吞介导内吞特异性特异性高效性高效性第二节第二节 抗原加工递呈途径抗原加工递呈途径Antigen Processing and Presentation Antigen Processing and Presentation PathwaysPathways MHCMHC类途径类途径 MHCM

13、HC类途径类途径 非经典途径非经典途径概述概述T T细胞不能直接识别游离蛋白细胞不能直接识别游离蛋白AgAg，只能通过只能通过TCRTCR识别识别AgAg肽肽-MHC-MHC分子复合物分子复合物CD4+T-AgCD4+T-Ag肽肽-MHC-MHC分子复合物分子复合物CD8+T-AgCD8+T-Ag肽肽-MHC-MHC分子复合物分子复合物YThe site of pathogen replication or mechanism of antigen The site of pathogen replication or mechanism of antigen uptake determine

14、s the antigen processing pathway useduptake determines the antigen processing pathway usedYCytosolic compartmentEndogenous processingEndogenous processing(Viral antigens)Vesicular CompartmentContiguous with extracellular fluidExogenous processingExogenous processing(Streptococcal,Mycobacterial antig

15、ens)INTRACELLULAR REPLICATIONEXTRACELLULAR ORENDOSOMAL REPLICATIONYEliminated by:Killing of infected cells by CTLCTL that use antigens generated by ENDOGENOUS PROCESSINGYEliminated by:Antibodies and phagocyteactivation by T helper cellsT helper cells that use antigens generated byEXOGENOUS PROCESSIN

16、GAntigens generated by endogenous and exogenous Antigens generated by endogenous and exogenous antigen processing activate different effector functionsantigen processing activate different effector functionsENDOGENOUS PATHOGENSEXOGENOUSPATHOGENS一、外源性抗原加工递呈途径一、外源性抗原加工递呈途径Exogenous processing and pres

17、entation Exogenous processing and presentation pathway pathway MHC class MHC class pathway pathway 外源性外源性AgAg经经MHCMHC类分子递呈类分子递呈阶段：阶段：外源性抗原的摄取、加工外源性抗原的摄取、加工MHCMHC类分子的合成及转运类分子的合成及转运MHCMHC类分子荷肽类分子荷肽递呈给递呈给CD4CD4+T T细胞细胞MHCMHC类途径类途径1 1、外源性抗原的摄取、加工处理、外源性抗原的摄取、加工处理Uptake and degradation of exogenous Uptake

18、 and degradation of exogenous antigensantigens APCAPC以胞吞作用摄入以胞吞作用摄入AgAg，形成内体，形成内体内体与溶酶体融合形成内体内体与溶酶体融合形成内体/溶酶体溶酶体AgAg被蛋白酶降解成被蛋白酶降解成AgAg肽肽抗原加工区室抗原加工区室（compartmentscompartments）YYPinocytosisPhagocytosisMembrane Ig receptor mediated uptakeYComplement receptormediated phagocytosisYFc receptor mediated ph

19、agocytosisUptake of exogenous antigensUptake of exogenous antigensAPCAPC以胞吞作用摄入以胞吞作用摄入AgAg，形成内体，形成内体EndosomesExogenous pathwayExogenous pathwayIncreasein acidityCell surfaceTo lysosomesUptakeProtein antigensIn endosomeCathepsin B,D and L proteases are activated by the decrease in pH2 2、MHCMHC类分子的合成及

20、转运类分子的合成及转运Biosynthesis and transportation of Biosynthesis and transportation of MHC classMHC class molecules molecules 粗面内质网中粗面内质网中MHCMHC类分子合成类分子合成与与IiIi链结合成链结合成 (IiIi)3 3复合物复合物Need to prevent newly synthesised,self proteins from binding to immature MHC Invariant chain stabilises MHC class II by bi

21、nding to the immature MHC class II moleculeIn the Endoplasmic ReticulumMHC class II maturation and invariant chainMHC class II maturation and invariant chainConceptionConception i i链链 a-associated a-associated i invariant chainnvariant chain，a a分子分子相关的不变链相关的不变链协助协助类分子折叠和装配类分子折叠和装配阻止阻止类分子与类分子与ERER中的新

22、合成的肽或内源性中的新合成的肽或内源性抗原肽结合抗原肽结合引导引导类分子进入内体类分子进入内体Structure of invariant chainStructure of invariant chainThree extended peptides each bind into the grooves of three MHC class II molecules to form the nonomeric complexCLass II associated Invariant chain Peptide(CLIP)A peptide of the invariant chain blo

23、cks the MHC molecule binding siteCLIP of invariant chainCLIP of invariant chain and chains of MHC class II moleculesCLIPConception CLIPCLIP ClClass ass-associated-associated i invariant chain nvariant chain p peptide eptide，类分子相关的不变链多肽类分子相关的不变链多肽 i i链中链中8181位至位至104104位氨基酸残基的肽段结构位氨基酸残基的肽段结构 能与所有能与所有M

24、HCMHC类分子抗原结合槽相结合类分子抗原结合槽相结合3 3、MHCMHC类分子荷肽类分子荷肽Peptide-loading of MHC class Peptide-loading of MHC class moleculesmolecules i i链引导下链引导下类分子进入类分子进入内体内体(MCMC)i i链降解，链降解，类分子肽结合槽中保留类分子肽结合槽中保留CLIPCLIP HLA-DM HLA-DM催化，催化，CLIPCLIP与肽结合槽解离与肽结合槽解离 HLA-DMHLA-DM编选，高亲和力肽与编选，高亲和力肽与类分子结合类分子结合AgAg肽肽-MHC-MHC类分子形成类分子形

25、成EndosomesCell surfaceUptakeClass II associated invariant chain peptide(CLIP)Class II associated invariant chain peptide(CLIP)(Ii)3 complexesdirected towardsendosomes byinvariant chainCathepsin L degrades Invariant chainCLIP blocks groove in MHC moleculeMHC Class IIcontaining vesiclesfuse with antig

26、encontaining vesiclesRemoval of CLIPRemoval of CLIP?How can the peptide stably bind to a floppy binding site?Competition between large number of peptidesHLA-DM catalyses the removal of CLIPHLA-DM catalyses the removal of CLIPMIIC compartmentMIIC compartmentHLA-DMHLA-DMReplaces CLIP with a peptide an

27、tigen using a catalytic mechanismSequence in cytoplasmic tail retains HLA-DM in endosomesHLA-DMHLA-DRConceptionMMC CM MHC class HC class c compartmentompartment，MHCMHC类分子区室类分子区室富含外源性抗原肽、富含外源性抗原肽、MHCMHC类分子、类分子、HLA-DMHLA-DM的的低低pHpH值的晚期内体值的晚期内体MHCMHC类分子荷肽主要场所类分子荷肽主要场所 HLA-DMHLA-DM的编选作用的编选作用 HLA-DMHLA-D

28、M可驱逐与可驱逐与类分子抗原结合槽低亲和类分子抗原结合槽低亲和力结合的肽，直至有高亲和力的肽与力结合的肽，直至有高亲和力的肽与类分类分子结合，才与子结合，才与类分子分离，使其抗原结合类分子分离，使其抗原结合槽恢复闭合状态。槽恢复闭合状态。HLAHLA这种对肽的选择作用称为这种对肽的选择作用称为HLA-DMHLA-DM的编选的编选作用，保证作用，保证类分子递呈高亲和力的外源类分子递呈高亲和力的外源性抗原肽性抗原肽。4 4、递呈给、递呈给CD4CD4+T T细胞细胞Presentation of exogenous antigenPresentation of exogenous antigenA

29、gAg肽肽-类分子经胞吐作用表达于类分子经胞吐作用表达于APCAPC表面表面供供CD4CD4+T T细胞识别细胞识别MIIC compartment sorts peptide-MHC complexes for surface expression or lysosomal degradationSurface expression of MHC class II-Surface expression of MHC class II-peptide complexespeptide complexesExported to the cell surface Sent to lysosomes

30、 for degradation 二、内源性抗原加工递呈途径二、内源性抗原加工递呈途径Endogenous processing and presentation Endogenous processing and presentation pathway pathway MHC class MHC class pathwaypathway 内源性内源性AgAg加工后由加工后由MHCMHC类分子递呈类分子递呈阶段：阶段：内源性内源性AgAg肽的产生及转运肽的产生及转运MHCMHC类分子荷肽类分子荷肽递呈给递呈给CD8CD8+T T细胞细胞MHCMHC类途径类途径1 1、内源性抗原肽的产生、内源

31、性抗原肽的产生Generation of endogenous antigenic Generation of endogenous antigenic peptidepeptide内源性抗原泛素化内源性抗原泛素化经蛋白酶体（经蛋白酶体（LMPLMP）降解为短肽）降解为短肽Crystal Structure Of The 20s ProteasomeCrystal Structure Of The 20s ProteasomeFrom YeastFrom YeastViewEnd onDegradation in the proteasomeDegradation in the proteas

32、omeThese components are induced by IFN-and replace constitutive components to confer proteolytic properties The components of the proteasome include MECL-1,LMP2,LMP7LMP2&7 encoded in the MHCProteasome cleaves proteins into hydrophobic and basic amino acidsCytoplasmic cellular proteins,including non-

33、self proteinsare degraded continuously by a multicatalytic protease of 28 subunits2 2、内源性抗原肽转运至内质网、内源性抗原肽转运至内质网Transportation of endogenous Transportation of endogenous antigenic peptide into ERantigenic peptide into ER经抗原加工相关转运体（经抗原加工相关转运体（TAPTAP）转运至）转运至ERERERCYTOSOLPeptide antigens produced in the

34、 cytoplasm are Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class Iphysically separated from newly formed MHC class INewly synthesisedMHC class I moleculesPeptides needaccess to the ER inorder to be loaded onto MHC class I moleculesER membraneLumen of ERC

35、ytosolTransporters associated withTransporters associated withantigen processing(TAP1&2)antigen processing(TAP1&2)Transporter has preference for 8-15 amino acid peptideswith hydrophobic,basic C terminiTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2Pept

36、ideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideER membraneLumen of ERCytosolTAP-1TAP-2PeptideATP-binding cassette(ABC)domainHydrophobictransmembranedomainPeptide antigensfrom proteasome3 3、MHCMHC类分子荷肽类分子荷肽Peptide-loading of MHC class Peptide-loading of MHC class moleculesmole

37、cules内质网内钙联蛋白、钙网蛋白协助下内质网内钙联蛋白、钙网蛋白协助下 MHCMHC类分子合成类分子合成tapasintapasin协助下协助下MHCMHC类分子与类分子与TAPTAP孔道孔道内侧口结合内侧口结合AgAg肽肽-MHC-MHC类分子复合物形成类分子复合物形成Endoplasmic reticulumCalnexin bindsto nascentclass I chainuntil 2-M bindsTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-

38、1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2Peptide2-M binds and stabilises floppy MHCTapasin,calreticulin,TAP 1&2 form a complex with the floppy MHCCytoplasmic peptides are loaded onto the MHC molecule and the structure becomes compactMaturation and lo

39、ading of MHC class IMaturation and loading of MHC class I4 4、递呈给、递呈给CD8CD8+T T细胞细胞Presentation of endogenous antigenPresentation of endogenous antigenAgAg肽肽-MHC-MHC类分子经高尔基体类分子经高尔基体通过胞吐作用表达于细胞表面通过胞吐作用表达于细胞表面供供CD8CD8T T细胞识别细胞识别Fate of MHC class IFate of MHC class ISent to lysosomes for degradation Exp

40、orted to the cell surfaceEndoplasmic reticulumTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2HSV protein blocks transportof viral peptides into ERSent to lysosomesfor degradation Evasion of immunity by interference with endogenous Evasion of immunity by interference wi

41、th endogenous antigen processingantigen processingSent to lysosomes for degradation Normally exported to the cell surfaceAdenoviralproteinretains MHCclass I in the EREvasion of immunity by interference withEvasion of immunity by interference withendogenous antigen processingendogenous antigen proces

42、sing三、非经典抗原加工递呈途径三、非经典抗原加工递呈途径Non classical pathwayNon classical pathway外源性抗原也可被外源性抗原也可被MHCMHC类分子递呈类分子递呈外源性抗原穿透细胞膜进入胞浆外源性抗原穿透细胞膜进入胞浆外源性抗原自内体逸出进入胞浆外源性抗原自内体逸出进入胞浆-以内源性抗原方式加工递呈给以内源性抗原方式加工递呈给CD8CD8+T T细胞细胞内源性抗原也可被内源性抗原也可被MHCMHC类分子递呈类分子递呈胞质内蛋白形成自吞小泡，与内体胞质内蛋白形成自吞小泡，与内体/溶酶体融合溶酶体融合 -以外源性抗原方式加工递呈给以外源性抗原方式加工递呈给CD4CD4+T T细胞细胞交叉致敏（交叉致敏（cross-primingcross-priming）专职性专职性APC APC 激活未致敏的肿瘤或病毒抗原特异激活未致敏的肿瘤或病毒抗原特异性性CD8+TCD8+T细胞的机制细胞的机制DCDC具有交叉致敏作用具有交叉致敏作用学习了抗原提呈细胞的特性和功能后，学习了抗原提呈细胞的特性和功能后，你是如何体会抗原提呈细胞的免疫学功你是如何体会抗原提呈细胞的免疫学功能和生物学意义的呢？能和生物学意义的呢？