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1、1,第11章 抗原的加工与递呈Antigen Processing & Presentation,2,T cells do not recognise native antigens,Y,Y,Y,Y,Y,Y,Proliferation and antibody production,No proliferation No cytokine release,Cross-linking of surface membrane Ig,3,Antigens must be processed in order to be recognised by T cells,T cell response,No
2、 T cell response,No T cell response,No T cell response,No T cell response,ANTIGEN PROCESSING,4,MHC directs the response of T cells to foreign antigens,Ag,MHC antigens PRESENT foreign antigens to T cells Cells that present antigen are ANTIGEN PRESENTING CELLS,5,Ag,B细胞,浆细胞,Ab,APC,Th细胞,Ag肽-MHC分子,T细胞,Tc
3、细胞,6,Contents,抗原递呈细胞 抗原加工递呈途径,7,第一节 抗原递呈细胞Antigen Presenting Cells,基本概念 抗原递呈细胞,8,一、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。,9,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
4、 有核细胞内加工，由MHC分子递呈,10,Listeria,外源性抗原 (exogenous 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,11,二、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,12,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
5、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MHC-类分子,13,14,1、树突状细胞（dendritic cell, DC）,典型树突状形态 功能最强的APC,15,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),16,并指状树突细胞,滤泡状 树突细胞,B细胞,17,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
6、噬弱 表达低水平的MHC分子、协同刺激分子和粘附分子,18,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DC(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,19,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,20,2、巨噬细胞(Macrophage, M),21,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）,22,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
7、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）,23,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,24,25,M摄取抗原途径,胞吞作用 吞噬 吞饮 受体介导内吞,26,模式识别受体 （pattern recognition receptors，PRR）,27,3、B细胞,28,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,29,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,30,概述,T细胞不能
8、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,31,32,33,Y,The site of pathogen replication or mechanism of antigen uptake determines the antigen processing pathway used,Cytosolic compartment Endogenous processing (Viral antigens),Vesicular Compartment Contiguous with extrace
9、llular fluid Exogenous processing (Streptococcal, Mycobacterial antigens),INTRACELLULAR REPLICATION,EXTRACELLULAR OR ENDOSOMAL REPLICATION,34,Y,Eliminated by: Killing of infected cells by CTL that use antigens generated by ENDOGENOUS PROCESSING,Eliminated by: Antibodies and phagocyte activation by T
10、 helper cells that use antigens generated by EXOGENOUS PROCESSING,Antigens generated by endogenous and exogenous antigen processing activate different effector functions,ENDOGENOUS PATHOGENS,EXOGENOUS PATHOGENS,35,一、外源性抗原加工递呈途径,Exogenous processing and presentation pathway MHC class pathway 外源性Ag经MH
11、C类分子递呈,36,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,37,1、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）,38,Y,Pinocytosis,Phagocytosis,Membrane Ig receptor mediated uptake,Complement receptor mediated phago
12、cytosis,Fc receptor mediated phagocytosis,Uptake of exogenous antigens,APC以胞吞作用摄入Ag，形成内体,39,Exogenous pathway,Protein antigens In endosome,Cathepsin B, D and L proteases are activated by the decrease in pH,40,41,2、MHC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
13、链结合成 (Ii)3复合物,42,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 II maturation and invariant chain,43,Conception,i链 a-associated invariant cha
14、in，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,44,Structure of invariant chain,Three extended peptides each bind into the grooves of three MHC class II molecules to form the nonomeric complex,45,CLass II associated Invariant chain Peptide (CLIP) A peptide of the invariant chain blocks th
15、e MHC molecule binding site,CLIP of invariant chain,46,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,47,3、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 A
16、g肽-MHC类分子形成,48,Class II associated invariant chain peptide (CLIP),(Ii)3 complexes directed towards endosomes by invariant chain,Cathepsin L degrades Invariant chain CLIP blocks groove in MHC molecule,MHC Class II containing vesicles fuse with antigen containing vesicles,49,Removal of CLIP,?,How can
17、the peptide stably bind to a floppy binding site?,Competition between large number of peptides,50,HLA-DM catalyses the removal of CLIP,MIIC compartment,HLA-DM Replaces CLIP with a peptide antigen using a catalytic mechanism,51,Conception,MC MHC class compartment，MHC类分子区室 富含外源性抗原肽、 MHC类分子、HLA-DM的低pH值
18、的晚期内体 MHC类分子荷肽主要场所,52,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。,53,54,4、递呈给CD4+T细胞,Presentation of exogenous antigen Ag肽-类分子经胞吐作用表达于APC表面 供CD4+T细胞识别,55,MIIC compartment sorts peptide-MHC complexes for surface expressio
19、n or lysosomal degradation,Surface expression of MHC class II- peptide complexes,56,57,58,二、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,59,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,60,1、内源性抗原肽的产生,Generation of endogenous antigenic peptide 内源性抗原泛素化
20、 经蛋白酶体（LMP）降解为短肽,61,62,63,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, LMP7 LMP2 & 7 encoded in the MHC Proteasome cleaves proteins into hydrophobic and b
21、asic amino acids,Cytoplasmic cellular proteins, including non-self proteins are degraded continuously by a multicatalytic protease of 28 subunits,64,2、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,65,66,ER,CYTOSOL,Peptide antigens produced in the cytoplasm
22、are physically separated from newly formed MHC class I,67,Transporters associated with antigen processing (TAP1 & 2),Transporter has preference for 8-15 amino acid peptides with hydrophobic, basic C termini,68,3、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
23、分子与TAP孔道内侧口结合 Ag肽-MHC类分子复合物形成,69,Calnexin binds to nascent class I chain until 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 load
24、ing of MHC class I,70,4、递呈给CD8+T细胞,Presentation of endogenous antigen Ag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,71,Fate of MHC class I,72,73,74,Evasion of immunity by interference with endogenous antigen processing,75,Evasion of immunity by interference with endogenous antigen processing,76,77,三、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,78,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,79,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？,