免疫C10-121012.ppt

,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,T,细胞的分化发育,表面分子,T,细胞亚群,T,细胞功能,第,12,章,1,White Blood Cells,Platelets(stained purple),a T-Lymphocyte(stained,green),and a Monocyte white cell(stained gold)as seen through a,scanning electron microscope.2000 Dennis Kunkel,Ph.D.,2,Severe combined immunodeficiency(SCID)is a,rare,potentially fatal syndrome in which there is,combined absence of T and B-lymphocyte function,To be life threatening,that may caused by,pneumonia,meningitis or,bloodstream infections.,need to be looked after,in a sterile environment,3,6,第二节,表面分子及其作用,-抗原受体复合物,-辅助受体,-协同刺激分子,7,T cell activation by Ag,APC,T,Signal 1 antigen&antigenreceptor,Signal 2,ACTIVATION,Costimulatory molecules are expressed by most APC including dendritic cells,monocytes,macrophages,B cells etc.,but not by cells that have no immunoregulatory functions such as muscle,nerves,hepatocytes,epithelial cells etc.,8,-TCR,-CD3,一、抗原受体复合物,复合物组成,两种分子,9,1.TCR,TCR,组成,由,两条肽链组成，,-,、,链,（,95%T,细胞表达，,-T细胞,）,-,、链,（,5%T,细胞表达，,-T细胞,）,属于膜蛋白，表达与T细胞膜表面：,-膜外区：,V区、C区(Ig Fab),-跨膜区:,带正电荷，与,CD3的负,电荷形成传递信,号的盐桥。,-胞浆区：,很短，,3,个氨基酸残基，不能向细胞内,传递信号。,10,TCR&BCR,11,特异性识别、结合抗原。,转导抗原刺激信号给CD3分子。,TCR,功能,12,2.CD3,组成,由3个二聚体（6条肽链）组成：,-,e,-,e,-,e,-,e,-,z,-,z,-,z,-,h,-,z,-,h,属于膜蛋白，,-膜外区：很短。,-跨膜区:带负电荷，与,CD3的正,电荷形成盐桥，接受,TCR的Ag信号。,-胞浆区：较长，含有,ITAM,，可将Ag信号向内传递。,13,CD3,TCR,14,The cytoplasmic domains of the CD3 complex contain 10,Immunoreceptor Tyrosine-based Activation Motifs,(,ITAM,S)-2 tyrosine residues separated by 9-12 amino acids-YXXL/VX,6-9,YXXL/V,As with B cell receptors,immunoreceptor tyrosine-based activation motifs(ITAMs)are involved in the transmission of the signals from the receptor,and require clustering of TcR/CD3 and the CD4 or CD8 co-receptors,CD3,ITAM,15,CD3,功能,转导,TCR,获得的,Ag,刺激信号,至,T,细胞内。,16,二、T细胞辅助受体,1.CD4：,CD4,+,T,细胞,例,如,Th,2.CD8：,CD8,+,T,细胞,例,如,Tc,17,1、CD4,-单链跨膜蛋白。,-,4,个功能区。,-,D1、D2,能,与,MHC-II,的,b,2,结合，辅助,TCR,识别,Ag,。,18,2、CD8,-,a,、,b,2条肽链。,-每链条有1个功能区，,能,与,MHC-I,分子的,a,3,结合，,辅助,TCR,识别,Ag,。,19,T细胞辅助受体,CD4/CD8,的,功能,1.,结合,MHC,辅助,TCR,识别抗原。,2.,参与,TCR,转导,Ag,活化信号。,20,Th,通过,CD4,识别自身,APC,的,MHC-II,，,Tc,通过,CD8,识别自身,APC,的,MHC-I,是,TCR,识别,Ag,的必要环节,否则,TCR,不能与,Ag,有效结合。,是,T,细胞与,APC,作用时具有,自身,MHC,限制性,的原因。,MHC-I,MHC-II,21,CD4/CD8促进CD3的ITAM磷酸化,22,APC,T,Signal 1 antigen&antigenreceptor,Signal 2,ACTIVATION,三、,T细胞,协同刺激分子,23,L,24,T细胞协同刺激分子,25,Signal,Signal,+Signal,Double Signals&Other Accessory Molecules,Act&Proliferation,Anergy,26,27,T细胞协同分子功能,转导协同刺激信号,第二信号,，促进T细胞完全活化,增殖、分化,。,28,第一节,T,细胞的分化发育,29,一、,在胸腺的分化发育,30,31,1.Pro-T(,TN-T),-CD3,-,-CD4,-,、,CD8,-,-TCR,b,基因重排,2.Pre-T(DN-T),-CD3 low,-CD4,-,、CD8,-,-TCR,b,pT,a,表达,-TCR,a,基因重排,一、,在胸腺的分化发育,32,3.DP-T,-CD3 low,-CD4,+,，,CD8,+,-TCR,ab,low,-,阳性选择。,4.SP-T(,未成熟T,),-CD3+,-CD4+CD8-or CD4-CD8+,-TCR,ab,-阴性选择,33,5.SP-T(,成熟T,),-CD3+,-CD4+CD8-or CD4-CD8+,-TCR,ab,34,e,35,36,Abbas,37,阳性选择,Concept,CD4,或,CD8,以适当亲和力与自身,MHC,分子结合的胸腺细胞可以继续发育，而与自身,MHC,分子不能结合或亲和力过高的胸腺细胞被删除的过程。,Result,产生自身,MHC,限制性的,T,细胞库,。,使胸腺细胞能够由,DP-T,发育为,SP-T,细,胞。,38,Positive selection,Thymic epithelial cell,Peptide is a partial agonist Thymocyte receives,a partial signal and is rescued from apoptosis.,Survive,CD8,MHC-I,TCR,T cell,Die,39,CD4+,CD8+,T,MHC-I,Epith.,Properly,binding,CD4-,CD8+T,CD4+,CD8+T,MHC-II,Epith.,CD4+,CD8-,T,Properly,binding,No/Strongly,binding,Apoptosis,Positive selection,40,阴性选择,TCR,能与自身,MHC,分子所提呈的,Ag,肽牢固结合的胸腺细胞，在发育过程中被删除的过程。,Result,保证,T细胞库中不含有针对,各种自身分子的T细胞克隆，即T细胞获得中枢免疫耐受。,Concept,41,Negative selection,Thymic epithelial cell,Thymocyte receives a powerful signal and,undergoes apoptosis.,MHC-I,TCR,T cell,CD8,Die,42,TCR-T cell,Ag-MHC-I-APC,No,binding,Mature CD8+T,Ag-MHC-II-APC,No,binding,Mature CD4+T,TCR-T cell,High affinity,binding,Apoptosis,Negative selection,43,T(,初始T)细胞受Ag刺激后分化为不,同的功能亚群：,-Th、Tc,-Treg,-,记忆,T(memory T),二、,在外周免疫器官的分化发育,44,第三节,T 细 胞 亚 群,45,T细胞 由不同的T细胞亚群组成。,T细胞亚群的划分,依据有多种：,功能、表面分子、分化发育阶段、,应答状态、其它。,46,47,一.应答状态亚群,1.初始T细胞：,(1)来源：骨髓。,(2)活化状态:,未受过Ag刺激;静止状,态;,参与淋巴细胞再循环.,(3)功能:受Ag刺激后分化为效应T,细胞和记忆T细胞.,48,2.效应T细胞：,(1),来源：由,初始T细胞经Ag刺激,后分化、增殖而成.,(2)活化状态：,经Ag刺激后激活.,(3)功能：发挥免疫应答效应.,49,3.记忆T细胞：,(1),来源：由,初始T细胞经Ag刺激,后分化、增殖而成.,(2)活化状态：未激活.,(3)功能：,长期保持对Ag初次刺激的特,异性反应能力，再遇相同Ag,时迅速活化.,50,二.TCR类型亚群,ab,T,与,gd,T,细 胞 的 特 性 比 较,51,三.功 能 亚 群,1.Th：,CD4,+,(1)Th1：辅助细胞免疫,：,增强M,f,抗胞内病原体能力。,(2)Th2:辅助体液免疫,：,增强B细胞的免疫应答功能。,(3)TH17:辅助固有免疫,：,增强炎症反应。,52,2.Tc：,CD8,+,介导细胞免疫：直接杀伤靶细胞。,53,3.Treg：抑制免疫应答,(1)nTreg:,-由胸腺细胞分化。,-CD4+CD25+Foxp3+,-抑制自身免疫病。,-机制：细胞-细胞接触。,(2)iTreg:,-由初始T/nTreg分化。,-CD4+CD25-/+Foxp3-/+,-抑制自身炎症反应。,-机制：细胞因子。,-Th3:,分泌TGF-,b,抑制Th1,-Tr1:,分泌IL-10抑制M,f,54,本章复习思考题,1.,阳性选择、阴性选择的概念,及结果。,2.,ab,T,与,gd,T,细胞的特性比较,。,55,