特异性免疫细胞

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/B,淋 巴 细 胞,第 八 章,二零一零年十一月,医学免疫学,授课教师：方敏,基 本 概 念,免疫细胞：,所有参与免疫应答或与免疫应答有关的细胞及其前体，包括造血干细胞、APC、淋巴细胞、粒细胞、肥大细胞和红细胞。,淋巴细胞（lymphocyte）:,是一群异质性的构成免疫系统的主要细胞，如T细胞、B细胞和NK细胞等。,The types and subsets of lymphocytes,55%,25%,10%,10%,5%,主 要 内 容,T,淋巴细胞,-T,细胞的分化发育,-T,细胞的表面标志,-T,细胞亚群及功能,B,淋巴细胞,来源于骨髓,在胸腺（thymus）,内发育成熟移行至外周淋巴组织执行特异性细胞免疫应答，参与对TD抗原的体液免疫应答。,重要事件,* 功能性TCR形成（基因重排）；,* 阳性选择,* 阴性选择。,意义,* 获得功能性与多样性的TCR；,* 获得MHC的限制性；,* 获得对自身抗原的耐受性。,T淋巴,细胞的发育,The thymus is required for T cell maturation,Athymic mice (,nude,) and humans (DiGeorge syndrome),are immunodeficient due to a lack of T cells,Neonatal thymectomy,No mature T cells,In adult,No thymectomy,Mature T cells,In adult,The thymus matures T cells after,birth, but early in life,Remove Thymus,Mature T & B cells,Adult,Neonate,No T cells,Mature B cells present,T cells not yet left thymus,The thymus is needed to generate mature T cells,The thymus,Lobulated structure with a,STROMA,of epithelial cells & connective tissue,Stroma provides a microenvironment for T cell development & selection,Lobules differentiated into an outer,CORTEX,& inner,MEDULLA, both filled with bone-marrow-derived,THYMOCYTES,Cortex,Medulla,Cortical,epithelial cell,Medullary,epithelial cell,Dendritic cell,Thymocyte,Macrophage,* 胸腺基质细胞：黏附胸腺细胞，产生细胞因子（IL-1,6,7)和胸腺激素促进T细胞分化发育,* DC、巨噬细胞和胸腺上皮细胞：向T细胞提呈抗原肽/MHC分子,Mouse,thymus,5,x 10,7,per day,T cells mature in the thymus but most die there.,98%,of cells die in the thymus without inducing any inflammation or any change in the size of the thymus.,Thymic macrophages phagocytose apoptotic thymocytes.,2,x 10,6,per day,Constant,1-2 x 10,8,cells,Y,T,Y,Y,T,T,APC,Harmful,Useless,Useful,Y,T,?,Positively,select,Negatively,select,Wholly self-reactive and useless T cells are removed MHC-restricted are retained,THYMUS,Y,T,Y,T,Y,Y,Y,Y,T,T,Y,Y,T,T,Y,Y,Y,T,T,T,Y,Y,Y,Y,T,Y,T,T,T,Random TcR,repertoire,ensures diversity,Y,T,Y,T,Y,T,Neglect,98%,T cell development is marked by cell surface,molecule changes,As T cells mature in the thymus they change their expression of TcR-associated molecules and co-receptors.,These changes can be used as markers of their stage of maturation,CD3/TcR-,CD4-, 8-,Double,negative,CD3+,TcR,-chain +,pre-TcR,+ (pT,CD4+, 8+,Large,double,positive,CD3+,TcR,+,CD4+,CD8+,Small,double,positive,TcR+,CD3+,CD4-, 8-,CD3+,TcR,+,CD4+,Single,positive,CD3+,TcR,+,CD8+,Single,positive,How are MHC restricted cells selected from the immature T cell repertoire?,TcR OK,MHC OK,TcR wrong,MHC OK,Useful,Useless,清除无用的T细胞,T细胞不能识别胸腺皮质上皮细胞提呈的肽/MHC复合物，即发生凋亡。,获得MHC限制性,DP细胞的CD4结合皮质胸腺上皮细胞的MHCII类分子，CD8丢失，成为CD4T细胞；而CD8结合MHCI类分子，则CD4丢失，成为CD8T细胞。,清除自身反应性（有害）T细胞,DP细胞TCR识别,经阳性选择的T细胞与髓质DC和巨噬细胞提呈的自身肽/MHC复合物高亲和力结合，则发生凋亡。,阳性选择：,DP,细胞,TCR,与胸腺皮质上皮细胞表面的,MHCI/II,类分子以适当亲和力结合，分化为,CD8/CD4,的,SP,细胞；不能结合或高亲和力结合的,DP,细胞发生凋亡。,阴性选择,:,能与,DC,或,M,提呈的自身肽,/,MHC,复合物高亲和力结合的,SP,细胞，发生凋亡；而不能识别抗原的,SP,细胞则发育成熟。,发育过程：,双阴性细胞（,DN,CD4,-,CD8,-,）,双阳性细胞（,DP,，,TCR,+,CD4,+,CD8,+,）,阳性选择（获得,MHC,限制性）,和,阴性选择（获得自身耐受）,成熟的单阳性细胞,(,CD4T,和,CD8T,细胞）,T,细胞的发育,主 要 内 容,T,淋巴细胞,-T,细胞的分化发育,-T,细胞的表面标志,-T,细胞亚群及功能,B,淋巴细胞,Menu,F,B,TCR/CD3 complex,immunoreceptor tyrosine-,based activation motif,T cell co-receptor molecules,CD8,MHC Class I,MHC Class II,3,2,TcR,TcR,CD4,Lck PTK,Lck PTK,CD4 and CD8 can increase the sensitivity of T cells to,peptide antigen MHC complexes by 100 fold,Inhibition of T cell activation by CTLA-4,Menu,B,LFA-1/ICAM-1,CD2/LFA-3,T细胞表面标志及其功能,T细胞表面受体：,TCR-CD3复合物,CKR,病毒受体（HIV受体CD4）,丝裂原受体(PHA、ConA、PWM),T细胞表面抗原：,MHC: I,类分子，活化后II类分子,CD分子：,共受体（CD4和CD8）,协同刺激分子(CD28/CTLA-4、CD40L),黏附分子(LFA1,和CD2),主 要 内 容,T,淋巴细胞,-T,细胞的分化发育,-T,细胞的表面标志,-T,细胞亚群及功能,B,淋巴细胞,T细胞的分类,按,TCR,二肽链组成分类,按,CD4,和,CD8,表达分类,按,T,细胞功能分类,按分泌的细胞因子谱分类,TCR,T细胞和TCR,T细胞特性的比较,CD4,+,T与CD8,+,T细胞的比较,CD4,+,T细胞 CD8,+,T细胞,表型 CD3,+,CD4,+,CD8,-,CD3,+,CD8,+,CD4,-,识别抗原肽 13,18AA 8,10AA,MHC限制性 MHC-II类分子 MHC-I类分子,Th + -,Tc + +,CD8,MHC-I,CD4,MHC-II,CD4,MHC-II,CD4,+,T,细胞,Th0，Th1，Th2,CD4,+,CD25,+,Tr,Cytokine profile of,helper T lymphocyte subsets,Th1,Th2,Th0,IL-3,GM-CSF,IL-4,IL-5,IL-6,IL-10,TGF-,IL-3,GM-CSF,IL-2,IFN-,TNF,TNF-,High IL-2,Low IL-4,IFN-,CCR3,CCR5,IL-4,IL-12,IFN-,g,Effector functions of Th1 cells,pCTL,CTL,Lysis of target,Induction of CTL differentiation,IFN-,Inflammatory Th1,T cell,Th1,Macrophage,Activated macrophage,Killing of intracellular bacteria,IL-12,IFN-,IL-2,Th2,Th0,V D J C,C,Ig isotype switch factor,IgG,V D,J C,IgE,CD40L-CD40,+ IL-4,B,Effector functions of Th2 cells,IL-4 also enhances IgM,hu,IgG4 and,mu,IgG1,Counter regulation of Th cell subsets,Balanced response,Th2,IFN-,IL-10,-,-,Th1,Th2 Dominant,Th1,IL-10,Th2,-,Th1 Dominant,Th2,Th1,IFN-,-,Humoral immunity,Cell mediated immunity,Th1 & Th2 polarisation may be influenced,by the type of infection,IL-12,IFN-,Macrophage,NK cell,IL-4,Mast cell,Th1,Th2,Th0,IFN-,CD4,+,CD25,+,Tr,细胞,(,regulator T cell),特征：,-抑制CD4T,和CD8T,细胞 活化与增殖,-直接接触性抑制；,-CTLA-4, mTGF-,b,;,-,下调,APC,的,B7,特异性介导靶细胞裂解或凋亡的机制为,释放穿孔素，致靶细胞裂解、死亡；,释放颗粒酶，借助穿孔素的孔道进入靶细胞，靶细胞凋亡；,高表达,FasL,，,通过,Fas/FasL,途径导致细胞凋亡。,CD8,+,杀伤性T细胞,（,Cytotoxic T lymphocyte, CTL or cytotoxic T cell, Tc,）,Menu,F,B,Menu,F,B,CD4,+,CTL,部分CD4,+,Th1也具有细胞毒作用,生物学特点：,仅在活化阶段受MHC-类分子限制，而效应 阶段无限制；,无抗原特异性，主要是旁观者杀伤效应；,主要通过FasFasL途径诱导细胞凋亡；,主要清除活化的APC和T细胞 负调节,Suppressor cells?,CD4+,Th,CD8+,Ts,+,-,TcR-containing, MHC-restricted,“suppressor factors”,TcR-containing, MHC-restricted,“helper factors”,1970,s & 1980s mechanism (now superseded),T cells produce cytokines that inhibit the induction of T cells,High,IL-10,CD4,Tr1,IL-10,TGF-,CD8,No IL-2,or IL-4,1990,s mechanism,NK1.1,+,T,细胞,广泛分布于骨髓、肝、脾、胸腺和淋巴结中,表型：,NKP.PIC（NK1.1）、TCR/CD3复合物,生物学功能及特征：,1.TCR识别由CD1分子提呈的脂类和糖类抗原；,2.非特异性细胞毒作用，不受MHC限制；,3.免疫调节作用：产生IL-4或IFN-,g,影响Th1和Th2的分化。,主 要 内 容,T,淋巴细胞,B,淋巴细胞,-B,细胞的分化发育,-B,细胞的表面标志,-,B,细胞亚群及功能,The discovery of B cell immunity,1954 -,Bruce Glick, Ohio State University,Studies on the function of a lymphoid organ in the cloacal region of the chicken the bursa of Fabricius,Bursectomy no apparent effect,Bursectomised chickens were later used in experiments to raise antibodies to,Salmonella,antigens,None of the bursectomised chickens made anti-Salmonella antibodies,Bursa was later found to be the organ in which antibody producing cells developed antibody producing cells were thereafter called B cells,Mammals do not have a bursa of Fabricius,B 细胞的发育,B,细胞在胎肝和骨髓发育成熟,进入外周淋巴组织 遇到抗原在,生发中心增殖、突变、选择, 抗体亲和力成熟，Ig类型转化，产生记忆B和浆细胞 产生抗体，介导体液免疫,主要事件,*,功能性,BCR,形成（基因重排，骨髓）,*,阴性选择（骨髓）,*,阳性选择,（,生发中心）,意义,* BCR,多样性,* 获得自身耐受,*,BCR与,抗体亲和力成熟、,Ig,类型转换、记,忆,B,细胞和浆细胞的产生,Transfer foetal,liver cells,Origin of B cells and organ of B cell,maturation,No Mature,B cells,After birth, development continues in the bone marrow,Normal bone marrow,Defective bone marrow,Mature B cells,in periphery,B cell development starts in the foetal liver,Menu,F,B,The stages of B cell development are distinguished by the expression of immunoglobulin chains and particular cell-surface proteins.,阴性选择,生发中心,Control Of Anti-Self B Cells,Primary Follicles become,secondary follicleswhen germinal centres develop,Dark zone,Light zone,B,T,Follicular dendritic,cells capture antigen on its surface, present to,B cells,Germinal Centre Microanatomy,1.,B cells (centroblasts) downregulate,surface Ig, proliferate, somatically hypermutate their Ig V genes.,AFFINITY MATURATION,2.,B cells (centrocytes) upregulate,surface Ig, stop dividing and,recognize antigen on FDC,receive costimulatory signals,from Th cells,3.,Apoptosis of,self-reactive &,unselected cells,4.,Selected cells leave lymph,node as memory,cells or plasma cells,B,B细胞的分化发育过程,抗原非依赖期（骨髓）,祖,B (VDJ/H),前,B(VJ/L;,胞浆,m),未成熟,B(mIgM,),成熟,B (,mIgM,and,mIgD,),阴性选择（骨髓）,未成熟,B(IgM,)+,自身抗原,克隆清除或无能,自身耐受,抗原依赖期（外周淋巴器官）,成熟,B+,抗原,活化增殖,在生发中心发育,浆细胞和记忆,B,阳性选择（生发中心）,活化,B,增殖,BCR,可变区体细胞超突变,突变,B,与,FDC,表面抗原高亲和力结合,选择存活,导致,BCR,及抗体亲和力成熟，抗体类型转换，产生浆细胞和记忆,B.,主 要 内 容,T,淋巴细胞,B,淋巴细胞,-B,细胞的分化发育,-B,细胞的表面标志,-,B,细胞亚群及功能,Co-stimulatory molecules on B cells,B细胞的表面标志,B细胞表面受体,BCR-Ig/Ig复合物,CKR：,IL-1R、IL-2R、IL-4R、IL-5R,等,CR：CR1和CR2,FcR:Fc,g,RII、Fc,a,R、Fc,m,R、Fc,e,R,丝裂原受体：LPS、PWM,B细胞表面抗原,MHCI/II,CD,分子：,共受体：,CD19、CD21、CD81,协同刺激分子：,CD40、B7-1/2,主 要 内 容,T,淋巴细胞,B,淋巴细胞,-B,细胞的分化发育,-B,细胞的表面标志,-B,细胞亚群及功能,CD5,Two B cell lineages,B,B cell precursor,B,Mature B cell,B2 cells,Plasma cell,Y,Y,Y,Y,Y,Y,Y,Y,Y,PC,IgG,B,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,IgM - no other isotypes,B,Distinct B cellprecursor,?,?,B1 cells,Primitive B cells found in pleura and peritoneum,Comparison of B-1 and B-2 cell properties,Property,B-1 cellsB-2 cells,V region repertoire,RestrictedDiverse,Location,Peritoneum/pleuraEverywhere,Renewal,Self renewal in situBone marrow,Spontaneous Ig production,HighLow,Isotypes,IgMIgM/G/A/D/E,Carbohydrate specifity,Yes Rarely,Protein specificity,RarelyYes,Need T cell help,NoYes,Somatic hypermutation of Ig,NoHigh,Memory development,NoYes,CD5,B,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,Y,IgM,B-1,细胞的主要生物学功能,-,主要识别,TI-2抗原的多糖类物质，如荚膜多糖，聚合鞭毛素等；,- 参与对多种细菌（尤其体腔中）的抗感染免疫；,- 产生低亲和力,IgM类的生理性自身抗体，参与对衰老、蜕变自身细胞的清除；,- 通过产生IgM类自身抗体参与某些自身免疫病的发生,B,Mature B-2 B cell,CD5,-,B-2,细胞的主要生物学功能,- 参与体液免疫应答：,BC+Ag,在Th,辅助下, 活化增殖,分化浆细胞 产生高亲和力抗体,- 抗原提呈：,BC用BCR摄取Ag, 处理肽+MHCII, 提呈抗原给CD4T,细胞，提供协同信号,- 免疫调节：,活化BC,产生多种细胞因子，参与免疫调节,Y,Y,Y,Y,Y,Y,IgG,小 结,T细胞发育的阳性和阴性选择。,T、B,细胞的表面标志及其功能。,T、B细胞的亚类及功能。,