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1、第11章 抗原的加工与递呈Antigen Processing&Presentation,T cells do not recognise native antigens,Y,Y,Y,Y,Y,Y,Proliferation and antibody production,No proliferationNo cytokine release,Cross-linking of surface membrane Ig,Antigens must be processed in orderto be recognised by T cells,T cellresponse,No T cellresp
2、onse,No T cellresponse,No T cellresponse,No T cellresponse,ANTIGENPROCESSING,MHC directs the response of T cells toforeign antigens,Ag,MHC antigens PRESENT foreign antigens to T cellsCells that present antigen are ANTIGEN PRESENTING CELLS,Ag,B细胞,浆细胞,Ab,APC,Th细胞,Ag肽-MHC分子,T细胞,Tc细胞,Contents,抗原递呈细胞抗原加工
3、递呈途径,第一节 抗原递呈细胞Antigen Presenting Cells,基本概念 抗原递呈细胞,一、基本概念,抗原加工与递呈（Antigen processing and presentation）抗原加工是指蛋白质抗原在细胞内被降解成能与MHC结合的肽的过程。抗原递呈是指MHC分子与抗原肽结合，将其展示于细胞表面供T细胞识别的过程。,内源性抗原（endogenous antigens）指细胞内产生的蛋白质抗原细胞产生的自身固有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，即肿瘤抗原有核细胞内加工，由MHC分子递呈,Listeria,外源性抗原(exogeno
4、us antigens)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在吞噬体和内体中生长的病原体摄入的自身蛋白抗原递呈细胞内加工，由MHC分子递呈,二、抗原递呈细胞,抗原递呈细胞(antigen presenting cell，APC)能够摄取、加工、处理抗原并将Ag信息递呈给抗原特异性淋巴细胞（T细胞）的一类免疫细胞。包括巨噬细胞、树突状细胞、成熟B细胞等,广义APC所有有核细胞表达MHC类分子专职APC(professional APC)M，DC，B细胞等表达MHC类分子兼职APC(non-professional APC)内皮细胞，上皮细胞，激活的T细胞等某些因素刺激后表达M
5、HC-类分子,1、树突状细胞（dendritic cell,DC）,典型树突状形态功能最强的APC,DC分类,根据起源淋巴系DC滤泡DC(FDC)髓系DC（CD11c+）郎格汉斯细胞(LC)并指状DC(IDC),并指状树突细胞,滤泡状树突细胞,B细胞,未成熟DC和成熟DC,未成熟DC(Immature DC)皮肤、胃肠道、呼吸道等上皮内及实质器官间质内摄取抗原并迁移至引流淋巴器官胞饮（吞饮）受体介导内吞吞噬弱表达低水平的MHC分子、协同刺激分子和粘附分子,成熟过程中的重要变化:表达趋化因子受体，获得向引流淋巴结迁移的能力加工递呈抗原，表达大量肽-MHC复合物协同刺激分子和粘附分子表达上调成熟D
6、C(Mature DC)淋巴结，脾及派氏集合淋巴管高表达MHC分子、协同刺激分子及粘附分子很强的抗原递呈能力,上皮组织中的LC捕捉外来抗原后即进入引流淋巴结的T细胞区，成为IDC,2、巨噬细胞(Macrophage,M),来源、分布,前单核细胞（骨髓）单核细胞（血液）巨噬细胞（组织器官）,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）,功能,吞噬消灭病原体加工递呈抗原，激发特异性免疫应答免疫应答的效应细胞,M摄取抗原途径,胞吞作用吞噬吞饮受体介导内吞,模式识别受体（pattern recogniti
7、on receptors，PRR）,3、B细胞,B细胞摄取抗原途径,加工递呈可溶性抗原BCR介导内吞特异性高效性,第二节 抗原加工递呈途径Antigen Processing and Presentation Pathways,MHC类途径 MHC类途径 非经典途径,概述,T细胞不能直接识别游离蛋白Ag，只能通过TCR识别Ag肽-MHC分子复合物CD4+T-Ag肽-MHC分子复合物CD8+T-Ag肽-MHC分子复合物,Y,The site of pathogen replication or mechanism of antigen uptake determines the antigen
8、processing pathway used,Cytosolic compartmentEndogenous processing(Viral antigens),Vesicular CompartmentContiguous with extracellular fluidExogenous processing(Streptococcal,Mycobacterial antigens),INTRACELLULAR REPLICATION,EXTRACELLULAR ORENDOSOMAL REPLICATION,Y,Eliminated by:Killing of infected ce
9、lls by CTL that use antigens generated by ENDOGENOUS PROCESSING,Eliminated by:Antibodies and phagocyteactivation by T helper cells that use antigens generated byEXOGENOUS PROCESSING,Antigens generated by endogenous and exogenous antigen processing activate different effector functions,ENDOGENOUS PAT
10、HOGENS,EXOGENOUSPATHOGENS,一、外源性抗原加工递呈途径,Exogenous processing and presentation pathway MHC class pathway 外源性Ag经MHC类分子递呈,阶段：外源性抗原的摄取、加工MHC类分子的合成及转运MHC类分子荷肽递呈给CD4+T细胞,MHC类途径,1、外源性抗原的摄取、加工处理,Uptake and degradation of exogenous antigens APC以胞吞作用摄入Ag，形成内体内体与溶酶体融合形成内体/溶酶体Ag被蛋白酶降解成Ag肽抗原加工区室（compartments）,Y,
11、Pinocytosis,Phagocytosis,Membrane Ig receptor mediated uptake,Complement receptormediated phagocytosis,Fc receptor mediated phagocytosis,Uptake of exogenous antigens,APC以胞吞作用摄入Ag，形成内体,Exogenous pathway,Protein antigensIn endosome,Cathepsin B,D and L proteases are activated by the decrease in pH,2、MH
12、C类分子的合成及转运,Biosynthesis and transportation of MHC class molecules 粗面内质网中MHC类分子合成与Ii链结合成(Ii)3复合物,Need to prevent newly synthesised,self proteins from binding to immature MHC,Invariant chain stabilises MHC class II by binding to the immature MHC class II molecule,In the Endoplasmic Reticulum,MHC class
13、 II maturation and invariant chain,Conception,i链 a-associated invariant chain，a分子相关的不变链协助类分子折叠和装配阻止类分子与ER中的新合成的肽或内源性抗原肽结合引导类分子进入内体,Structure of invariant chain,Three extended peptides each bind into the grooves of three MHC class II molecules to form the nonomeric complex,CLass II associated Invaria
14、nt chain Peptide(CLIP)A peptide of the invariant chain blocks the MHC molecule binding site,CLIP of invariant chain,Conception,CLIP Class-associated invariant chain peptide，类分子相关的不变链多肽 i链中81位至104位氨基酸残基的肽段结构 能与所有MHC类分子抗原结合槽相结合,3、MHC类分子荷肽,Peptide-loading of MHC class molecules i链引导下类分子进入内体(MC)i链降解，类分子
15、肽结合槽中保留CLIP HLA-DM催化，CLIP与肽结合槽解离 HLA-DM编选，高亲和力肽与类分子结合Ag肽-MHC类分子形成,Class II associated invariant chain peptide(CLIP),(Ii)3 complexesdirected towardsendosomes byinvariant chain,Cathepsin L degrades Invariant chainCLIP blocks groove in MHC molecule,MHC Class IIcontaining vesiclesfuse with antigencontai
16、ning vesicles,Removal of CLIP,?,How can the peptide stably bind to a floppy binding site?,Competition between large number of peptides,HLA-DM catalyses the removal of CLIP,MIIC compartment,HLA-DMReplaces CLIP with a peptide antigen using a catalytic mechanism,Conception,MCMHC class compartment，MHC类分
17、子区室富含外源性抗原肽、MHC类分子、HLA-DM的低pH值的晚期内体MHC类分子荷肽主要场所,HLA-DM的编选作用 HLA-DM可驱逐与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类分子结合，才与类分子分离，使其抗原结合槽恢复闭合状态。HLA这种对肽的选择作用称为HLA-DM的编选作用，保证类分子递呈高亲和力的外源性抗原肽。,4、递呈给CD4+T细胞,Presentation of exogenous antigenAg肽-类分子经胞吐作用表达于APC表面供CD4+T细胞识别,MIIC compartment sorts peptide-MHC complexes for sur
18、face expression or lysosomal degradation,Surface expression of MHC class II-peptide complexes,二、内源性抗原加工递呈途径,Endogenous processing and presentation pathway MHC class pathway 内源性Ag加工后由MHC类分子递呈,阶段：内源性Ag肽的产生及转运MHC类分子荷肽递呈给CD8+T细胞,MHC类途径,1、内源性抗原肽的产生,Generation of endogenous antigenic peptide内源性抗原泛素化经蛋白酶体（
19、LMP）降解为短肽,Degradation in the proteasome,These 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 acids,Cytopl
20、asmic cellular proteins,including non-self proteinsare degraded continuously by a multicatalytic protease of 28 subunits,2、内源性抗原肽转运至内质网,Transportation of endogenous antigenic peptide into ER经抗原加工相关转运体（TAP）转运至ER,ER,CYTOSOL,Peptide antigens produced in the cytoplasm are physically separated from newly
21、 formed MHC class I,Transporters associated withantigen processing(TAP1&2),Transporter has preference for 8-15 amino acid peptideswith hydrophobic,basic C termini,3、MHC类分子荷肽,Peptide-loading of MHC class molecules内质网内钙联蛋白、钙网蛋白协助下 MHC类分子合成tapasin协助下MHC类分子与TAP孔道内侧口结合Ag肽-MHC类分子复合物形成,Calnexin bindsto nas
22、centclass I chainuntil 2-M binds,2-M binds and stabilises floppy MHC,Tapasin,calreticulin,TAP 1&2 form a complex with the floppy MHC,Cytoplasmic peptides are loaded onto the MHC molecule and the structure becomes compact,Maturation and loading of MHC class I,4、递呈给CD8+T细胞,Presentation of endogenous a
23、ntigenAg肽-MHC类分子经高尔基体通过胞吐作用表达于细胞表面供CD8T细胞识别,Fate of MHC class I,Evasion of immunity by interference with endogenous antigen processing,Evasion of immunity by interference withendogenous antigen processing,三、非经典抗原加工递呈途径,Non classical pathway外源性抗原也可被MHC类分子递呈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-以内源性抗原方式加工递呈给CD8+T细胞内源性抗原也可被MHC类分子递呈胞质内蛋白形成自吞小泡，与内体/溶酶体融合-以外源性抗原方式加工递呈给CD4+T细胞,交叉致敏（cross-priming）专职性APC 激活未致敏的肿瘤或病毒抗原特异性CD8+T细胞的机制DC具有交叉致敏作用,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能和生物学意义的呢？,
