淋巴细胞及T细胞免疫应答总结课件(模板)

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,淋巴细胞,一、,T,淋巴细胞的表面分子及其作用,二、,T,淋巴细胞亚群,三、,T,淋巴细胞功能,T淋巴细胞 一、T淋巴细胞的表面分子及其作用,1,T,细胞是由一群功能不同的异质性淋巴细胞组成，由于它在胸腺内分化成熟故称为,T,细胞。,成熟,T,细胞由胸腺迁出，移居于周围淋巴组织中淋巴节的副皮质区和脾白髓小动脉的周围。,T,细胞执行特异性细胞免疫应答,并在,TD-Ag,诱导的体液免疫应答中发挥重要作用,T细胞是由一群功能不同的异质性淋巴细胞组成，由于它在胸腺内分,2,一、,T,淋巴细胞表面分子,一、T淋巴细胞表面分子,3,TCR,CD3,复合物,TCR,可分为,TCR,和,TCR,两种类型,结构相似,两条异源二聚体肽链藉二硫键组成的跨膜分子,每条肽链含,V,、,C,区，类似,Ig,结构,TCRCD3复合物TCR可分为TCR和TCR两种类,4,TCR-CD3,复合物,是,T,细胞抗原受体与一组,CD3,（,Gamma,Delta,Epsilon,Zeta,Eta,）分子以,非共价键,结合而形成的复合物，是,T,细胞识别抗原和转导信号的主要单位。,TCR,特异识别由,MHC,分子提呈的抗原肽，,CD3,分子转导,T,细胞活化的第一信号,TCR-CD3复合物,5,CD4,主要分布于成熟,Th,细胞、巨噬细胞、,DC,细胞等表面；,是,HIV,受体，与,APC,表面,MHC-II,分子非多态区结合,CD8,主要分布于成熟,Tc,细胞表面，与,APC,表面,MHC-I,分子,非多态区结合,既能加强,T,细胞与,APC,或靶细胞的相互作用，又能参与抗原刺激,TCR-CD3,分子信号转导,2. CD4,和,CD8,分子,2. CD4和CD8分子,6,加强,T,细胞与,APC,或靶细胞的相互作用,通过胞浆区的,CxCP,基序与,p56,lck,(,Src family tyrosine kinase LCK,),酪氨酸激酶相连，参与,T,细胞活化和增殖信号转导,CD4,和,CD8,T,细胞辅助受体,加强T细胞与APC或靶细胞的相互作用 CD4和CD8 T细,7,TCR识别抗原是MHCI类分子限制性,family related gene (GITR),contact-dependent manner either (a) directly or (b) indirectly via the APC.,掌握T细胞活化的条件,Recent studies have established that Th1 and Th2 effector cytokines, IFNg and IL-4, respectively, potently inhibit Th17 development.,Naive CD4 T cells (Tn) activated by antigen presented on immature DCs that do not produce IL-6 production are induced by TGF-b to express Foxp3 and develop into aTregs (top panel).,成熟CD2CD3CD4/CD8,Th细胞 根据所分泌的细胞因子不同，将其分为Th0、Th1和Th2亚型。,CD40/CD40L等,成熟T细胞由胸腺迁出，移居于周围淋巴组织中淋巴节的副皮质区和脾白髓小动脉的周围。,5、LFA-1和ICAM-1,既能加强T细胞与APC或靶细胞的相互作用，又能参与抗原刺激TCR-CD3分子信号转导,CD4+ T细胞或CD8+ T细胞,胸腺细胞经阳性选择赋予成熟T细胞在识别抗原时具有MHC限制性,Alternatively, TCR stimulation by antigen can induce Th17 cytokine production directly,细胞因子对Th1和Th2细胞的调节作用,Tns activated bymature,TLR-activatedDCsthat produceIL-6 are induced by TGF-b to upregulate IL-23R and become competent for IL-17 production and IL-23 signaling.,3）介导超敏反应（TDTH）,迟发型超敏反应性T细胞（TDTH）,(delayed type hypersencitivity, DTH),3.,协同（辅助）信号分子,协同信号分子,TCR-CD3,复合分子可提供第,1,信号,协同刺激信号,(costimulatouy signal),或第,2,信号,参与,T,细胞活化的协同刺激信号主要是,CD28-CD80/86,，,CTLA4-CD80/86,给予已活化,T,细胞抑制信号。,TCR识别抗原是MHCI类分子限制性3. 协同（辅助）信号分,8,CD40L,T,APC,CD28,CD80/86,CTLA4,CD40,LFA,1,ICAM,1,LFA,2,LFA,3,1,、,CD28,和,CTLA-4,(intercellular adhesion molecule-1),CD40LTAPCCD28CD80/86CTLA4CD40L,9,T,细胞与,APC,细胞间的主要辅助分子,T细胞与APC细胞间的主要辅助分子,10,2,、,ICOS,3,、,CD40L,4,、,CD2,5,、,LFA-1,和,ICAM-1,2、ICOS,11,4.,其它一些受体,丝裂原受体,细胞因子受体,病毒受体,4. 其它一些受体 丝裂原受体,12,二、,T,细胞分化发育,thymic corpuscle,二、T细胞分化发育thymic corpuscle,13,胸腺微环境,是诱导并调控,T,细胞分化发育的关键因素,胸腺基质细胞（,TSC,）,细胞因子,胸腺激素,胸腺微环境是诱导并调控T细胞分化发育的关键因素,14,双阴性期（,DN,）,原,T,细胞（,pro-T,）、前,T,细胞（,pre-T,）,TCR,、,CD3,、,CD4,、,CD8,双阳性期（,DP,）,TCR,、,CD3,low,、,CD4,、,CD8,单阳性期（,SP,）,TCR,、,CD3,、,CD4,TCR,、,CD3,、,CD8,成熟,T,细胞，具有识别抗原、介导免疫应答及参与免疫调节的功能,双阴性期（DN） 双阳性期（DP）单阳性期（SP）,15,1. T,细胞发育的,阳性选择,（,p,ositive selection,）,CD4,+,CD8,+,T,细胞胸腺基质细胞（表面,MHC,分子）,如果与,MHC-I,结合，最终分化为,CD8,+,T,细胞,如果与,MHC-II,结合则最终分化为,CD4,+,T,细胞,如果与,MHC,分子不结合则在胸腺皮质中凋亡,胸腺细胞经阳性选择赋予成熟,T,细胞在识别抗原时具有,MHC,限制性,1. T细胞发育的阳性选择（positive selecti,16,2. T,细胞发育的,阴性选择,（,n,egative,s,election,）,其,TCR,识别胸腺基质细胞表面高亲和力的,MHC,或,MHC-,自身抗原肽的,T,细胞克隆将发生凋亡,经阴性选择可清除自身反应性,T,细胞克隆,获中枢耐受,DP,或经阳性选择的,SP,的,T,细胞,2. T细胞发育的阴性选择（negative selecti,17,T,细胞在胸腺中的阳性选择和阴性选择,T细胞在胸腺中的阳性选择和阴性选择,18,CD28/B7促进IL-2基因转录、合成,contact-dependent manner either (a) directly or (b) indirectly via the APC.,参与T细胞活化的协同刺激信号主要是CD28-CD80/86，CTLA4-CD80/86给予已活化T细胞抑制信号。,(intercellular adhesion molecule-1),3）介导超敏反应（TDTH）,一、T淋巴细胞表面分子,TCR识别抗原是MHC类分子限制性,In the stages of an immune response against a microbial infection Tregs behave differently.,协同刺激信号(costimulatouy signal)或第2信号,T 细胞抗原受体及其识别抗原的特点,参与T细胞活化的协同刺激信号主要是CD28-CD80/86，CTLA4-CD80/86给予已活化T细胞抑制信号。,Nave CD4+ T cells can be,3）介导超敏反应（TDTH）,胸腺细胞经阳性选择赋予成熟T细胞在识别抗原时具有MHC限制性,4) 新型效应细胞：Th17,淋巴细胞凋亡的两种机制,T细胞发育的阴性选择（negative selection）,IL-23 signaling induces responsiveness to IL-18 and IL-1, which can act synergistically with IL-23 to induce Th17 cytokineproduction,加强T细胞与APC或靶细胞的相互作用,Generation and conversion of Treg cells in the tumor microenvironment,differentiated into different subsets of CD4+ T cells, including Th1, Th2, Treg and IL-17-producing T cells (Th17), depending upon the strength of antigen stimulation and cytokine milieu.,三、,T,细胞亚群,1,）根据,TCR,种类,T,、,T,细胞,在末梢血主要为,T,细胞可占,95%,，而,T,细胞只占,1%,10%,。,T,细胞为主要参予免疫应答的,T,细胞，两者特性和功能均不相同。,CD28/B7促进IL-2基因转录、合成三、T细胞亚群1）根,19,TCRT,和,TCRT,细胞,TCR,分布,表型,识别抗原,MHC,限制,功能,TCRT TCRT,极大多样性,60-70,外周淋巴组织,成熟,CD2CD3CD4/CD8,8,17aa,经典,MHC,Th,、,Tc,较少多样性,5-15,粘膜上皮,成熟大多数,CD2CD3,简单多肽、,HSP,、脂类、多糖,MHC,样分子,Tc,TCRT和TCRT细胞 TCRTCRT,20,2,）根据,T,细胞是否表达,CD4,或,CD8,分类,CD4+ T,细胞或,CD8+ T,细胞,TCRTCD4+,细胞：,CD2+,、,CD3+,、,CD4+,、,CD8-,TCR,识别抗原是,MHC,类分子限制性,TH0,、,Th1,和,Th2,、行使,Tc,、,Ts,功能,TCRTCD8+,细胞：,CD2+,、,CD3+,、,CD4-,、,CD8+,TCR,识别抗原是,MHCI,类分子限制性,行使,Tc,、,Ts,功能,2）根据T细胞是否表达CD4或CD8分类 TCRTCD,21,Th,细胞 根据所分泌的细胞因子不同，将其分为,Th0,、,Th1,和,Th2,亚型。,Tc,细胞 杀伤、分泌,IFN,、,IL-4,、,IL-5,和,IL-10,Ts,细胞,T,DTH,主要为,CD4,+,Th1,3,）功能性亚群：,Th,、,Tc,、,T,DTH,、,Ts,3）功能性亚群：Th、Tc、TDTH、Ts,22,4,）,初始,T,细胞和记忆性,T,细胞,记忆性,T,细胞表达,CD45RO,，而初始,T,细胞表达,CD45RA,5,）,NK1.1 T,细胞,其,TCR,识别的抗原是由,CD1,分子提呈的脂类和糖脂类抗原,Leukocyte Common antigen,4）初始T细胞和记忆性T细胞 Leukocyte Comm,23,1,）免疫调节功能（,Th1,、,Th2,、,Th3,、,Ts,、,Treg,）,2,）特异性杀伤功能（,CTL,、,Th1,、,T,）,3,）介导超敏反应（,T,DTH,）,4),新型效应细胞：,Th17,四、,T,细胞功能,1）免疫调节功能（Th1、 Th2 、 Th3、Ts 、 T,24,Naturally occurring CD4+CD25+ Treg cells (56%) GITR and Foxp3,a cellcell contact mechanism,Antigen-induced Tr1 and Th3 cells (IL-10) and/or (TGF-,b,),ck-dependent mechanism,no specific marker has,been identified.,Adaptively induced CD4+ Treg cells GITR and Foxp3,a cell contact dependent,or soluble factor-dependent,(other than IL-10and/or TGF-b),mechanism,glucocorticoid-induced TNFR,family related gene (GITR),CD8+ Treg cells,NKT regulatory T cells,Multiple subsets of Treg cells,Naturally occurring CD4+CD25+,25,Naturally occurring CD4+CD25+Foxp3+ Tregs,Development and function of naturally occurring CD4+CD25+ FoxP3+ regulatory T cells (nTregs). Development:bone marrow-derived CD4+ T cell precursors develop naturally,into nTregs upon beneficial TCR engagement by self-peptideMHC complexes and Foxp3 induction in the thymus. Upon instruction in the thymus, nTregs emigrate into the periphery as,functionally fully competent cells. Mode of action: upon TCR cross-linking, peripheral nTregs suppress the proliferation and IL-2 production by responder CD25CD4+ or CD8+ T cells in a,contact-dependent manner either (a) directly or (b) indirectly via the APC. In addition: nTregs may (c) condition DC to become tolerogenic and turn down the response of conventional T cells,on her part,Naturally occurring CD4+CD25+F,26,Extrathymic induction and function of adaptive regulatory T cells. Adaptive regulatory T cells (aTregs) differentiate from naive conventional CD4+ T cells either as a result of suboptimal antigenic stimulation by resting/immature DC, the,influence of suppressive cytokines like IL-10, TGF-b or cell contact-dependent interaction with activated nTregs (infectious tolerance). Their mode of action involves both cell contactdependent (Tr1 cells) and contact-independent suppressive activities (Th3 cells). Through the production of IL-10 and TGF-b they convert immature DC into tolerizing APC,Extrathymic induction and func,27,Fig. 3 Role of Tregs in early and late stages of microbial infections. In the stages of an immune response against a microbial infection Tregs behave differently. A Throughout the early phase of the response the suppressive activity of Tregs is turned down by effector T cell-derived IL-2 and microbial components such as TLR-ligands. Tregs respond to the stimulation by mature DC and proliferate.,Fig. 3 Role of Tregs in early,28,TCR与APC的特异性稳定结合,颗粒酶激活caspase 10,熟悉T细胞表面主要膜分子及其作用,Tns activated bymature,TLR-activatedDCsthat produceIL-6 are induced by TGF-b to upregulate IL-23R and become competent for IL-17 production and IL-23 signaling.,1、CD28和CTLA-4,活化CD8T、NK细胞，增强杀伤活性,诱导抗原： TD-Ag,Human IL-17 and IL-17R key features,CD8+ Treg cells,一、T淋巴细胞表面分子,经阴性选择可清除自身反应性T细胞克隆,T细胞在胸腺中的阳性选择和阴性选择,In addition: nTregs may (c) condition DC to become tolerogenic and turn down the response of conventional T cells,independently ofTCRstimulation.,A Throughout the early phase of the response the suppressive activity of Tregs is turned down by effector T cell-derived IL-2 and microbial components such as TLR-ligands.,（一）T细胞与APC的非特异性结合,5、LFA-1和ICAM-1,CD4+ T细胞或CD8+ T细胞,Th2细胞介导体液免疫,成熟T细胞由胸腺迁出，移居于周围淋巴组织中淋巴节的副皮质区和脾白髓小动脉的周围。,Leukocyte Common antigen,（二）活化T细胞发生凋亡，及时终止免疫应答,DP或经阳性选择的SP的T细胞,without a requirement for IL-23, IL-1, or IL-18.,抗原作用下跨膜分子及信号转导成分的多聚化,Compared with wild-type susceptible mice, mice deficient for IL-23 (Il23p19/) and both IL-23 and IL-12 (Il12p40/) failed to develop disease after antigenic challenge, whereas mice deficient for IL-12 (Il12p35/) developed more severe disease.,TCR 、CD3low、CD4 、CD8 ,掌握T细胞分群及不同亚群的生物学特性,抗原作用下跨膜分子及信号转导成分的多聚化,The cytokines associated with arrows indicate dominant cytokines involved in specification of each of the indicated lineages.,Caspase8 激活DNA 内切酶,掌握T细胞分群及不同亚群的生物学特性,T 细胞抗原受体及其识别抗原的特点,without a requirement for IL-23, IL-1, or IL-18.,诱导迟发型超敏反应，活化招募M在炎症局部浸润,contact-dependent manner either (a) directly or (b) indirectly via the APC.,T 细胞抗原受体及其识别抗原的特点,Diversification of CD4 T Cell Lineages,是HIV受体，与APC表面MHC-II分子非多态区结合,TCRT和TCRT细胞,一、T淋巴细胞表面分子,在末梢血主要为T细胞可占95%，而T细胞只占1%10%。,b At the late stage of the response, when the invading organism is cleared from the host, Tregs regain their suppressive function and participate in the silencing of the T cell response by acting on effector T cells and DC. Possibly, this late activity is also for the proper development of,memory T cells,TCR与APC的特异性稳定结合（二）活化T细胞发生凋亡，及时,29,Treg-based immune intervention strategies. Selective manipulation of Treg function is an emerging target for immune intervention strategies to either boost responses in cancer and microbial diseases or suppress those unwanted in autoimmunity, allergy, transplantation and pregnancy disorders. The transient,depletion of Tregs as well as their modulation by microbial agents may allow a transient reduction of Treg activity and enforce anti-tumor responses and immunity against viral infections. On the other hand their selective activation could diminish,chronic pathological immune responses,Treg-based immune intervention,30,Generation and conversion of Treg cells in the tumor microenvironment,Tumor cells not only provide antigenic stimulation for T cell activation but also interact with tumor-infiltrating innate immune cells to secrete crucial cytokines for T-cell differentiation. Nave CD4+ T cells can be,differentiated into different subsets of CD4+ T cells, including Th1, Th2, Treg and IL-17-producing T cells (Th17), depending upon the strength of antigen stimulation and cytokine milieu. It is known that combination of suboptimal antigen stimulation with TGF-b favors the conversion of naive T cells into Treg cells but blocks the generation of Th1 or Th2 cells. However, TGF-b plus IL-6 facilitate the conversion of naive T cells into,Th17 cells. Alternatively, naturally occurring CD4+CD25+ Treg cells directly derived from the thymus can cross-react with some antigens expressed by cancer cells, thus promoting their expansion and accumulation in the tumor microenvironment.,Generation and conversion of T,31,T-helper-cell differentiation,T-helper-cell differentiation,32,Human IL-17 and IL-17R key features,a Two isoforms (long and short).,Human IL-17 and IL-17R key fea,33,Therapeutic targets for autoimmune inflammatory,diseases are associated preferentially with the IL-23/Th17 pathway,Therapeutic targets,34,The pathogenic role for IL-23, not IL-12, in mouse models of autoimmunity,Studies by Cua and co-workers have demonstrated that disease development requires IL-23, but not IL-12, in EAE and CIA. Compared with wild-type susceptible mice, mice deficient for IL-23 (Il23p19/) and both IL-23 and IL-12 (Il12p40/) failed to develop disease after antigenic challenge, whereas mice deficient for IL-12 (Il12p35/) developed more severe disease.,The pathogenic role for IL-23,35,Model of Th1 versus Th17 lineage development from naive CD4 T cell precursors (Tn),This model emphasizes the distinct lineages leading to mature Th1 and Th17 effector cells (see main body of text for details). Question marks denote speculative or unknown aspects of Th17 differentiation that are yet to be defined.,Model of Th1 versus Th17 linea,36,Antagonistic cytokine networks control CD4 effector T-cell differentiation,Recent studies have established that Th1 and Th2 effector cytokines, IFNg and IL-4, respectively, potently inhibit Th17 development. Furthermore, TGF-b, a cytokine previously implicated in Treg development and function, appears to be required for Th17 development, both through indirect effects (blockade of IFNg and IL-4 production by cells of the innate immune system) and through direct effects on naive CD4 T-cell precursors (Tn).,Antagonistic cytokine networks,37,CD4+T,细胞分化和免疫调节细胞因子网络模式简图,CD4+T细胞分化和免疫调节细胞因子网络模式简图,38,Although functional CD4 T cell development has been dominated by the Th1-Th2 paradigm for nearly two decades, the number of defined lineages has now increased. The cytokines associated with arrows indicate dominant cytokines involved in specification of each of the indicated lineages. The cytokines listed below each cell type indicate key effector or regulatory cytokines produced by differentiated cells of that lineage or, in the case of nTreg, a contact-dependent mechanism of suppression. Tn: naive, postthymic CD4 T cell precursors; Tp: thymic precursors.Dotted lines represent less well-defined lineage relationships.,Diversification of CD4 T Cell Lineages,Although functional CD4 T cell,39,Model of Branching Th17 and Adaptive Treg Lineage Development,This model emphasizes distinct pathways leading to mature Th17 effector cells or Foxp3+ adaptive Tregs (aTreg), induced by a common requirement for TGF-b but differential effects of IL-6 and IL-23. Naive CD4 T cells (Tn) activated by antigen presented on immature DCs that do not produce IL-6 production are induced by TGF-b to express Foxp3 and develop into aTregs (top panel). Tns activated bymature,TLR-activatedDCsthat produceIL-6 are induced by TGF-b to upregulate IL-23R and become competent for IL-17 production and IL-23 signaling. IL-23 signaling induces responsiveness to IL-18 and IL-1, which can act synergistically with IL-23 to induce Th17 cytokineproduction,independently ofTCRstimulation.Alternatively, TCR stimulation by antigen can induce Th17 cytokine production directly,without a requirement for IL-23, IL-1, or IL-18.Dotted lines indicate possible positive feedback loops by which cytokine products of Th17 (IL-6) or aTreg cells (TGF-b1) may reinforce lineage development.,Model of Branching Th17 and Ad,40,CD4,辅助性,T,细胞,CD8,杀伤性,T,细胞,CD4辅助性T细胞,41,细胞因子对,Th1,和,Th2,细胞的调节作用,细胞因子对Th1和Th2细胞的调节作用,42,淋巴细胞及T细胞免疫应答总结课件(模板),43,Model of Branching Th17 and Adaptive Treg Lineage Development,3）介导超敏反应（TDTH）,CTLA4与CD28高同源性，与B7亲和力比CD28高20倍，结合后启动抑制信号，有效制约特异性T细胞克隆的过度增殖,免疫应答 抗原识别、反应、效应的全过程,TCR 、CD3 、CD4 、CD8 ,contact-dependent manner either (a) directly or (b) indirectly via the APC.,CD4+T细胞的双识别,5、LFA-1和ICAM-1,两条异源二聚体肽链藉二硫键组成的跨膜分子,Adaptively induced CD4+ Treg cells GITR and Foxp3,Leukocyte Common antigen,Tns activated bymature,TLR-activatedDCsthat produceIL-6 are induced by TGF-b to upregulate IL-23R and become competent for IL-17 production and IL-23 signaling.,坏死、凋亡、非溶解性途径,CD4 主要分布于成熟Th细胞、巨噬细胞、DC细胞等表面；,原T细胞（pro-T）、前T细胞（pre-T）,contact-dependent manner either (a) directly or (b) indirectly via the APC.,without a requirement for IL-23, IL-1, or IL-18.,（三）细胞因子促进T细胞充分活化,T细胞是由一群功能不同的异质性淋巴细胞组成，由于它在胸腺内分化成熟故称为T细胞。,Recent studies have established that Th1 and Th2 effector cytokines, IFNg and IL-4, respectively, potently inhibit Th17 development.,掌握效应性CD4+T细胞和CD8+T的功能,熟悉T细胞表面主要膜分子及其作用,3.,抑制性,T,细胞,4.,迟发型超敏反应性,T,细胞（,T,DTH,）,5. NK1.1,T,细胞,Model of Branching Th17 and Ad,44,掌握,TCR,分型与结构,掌握,T,细胞分群及不同亚群的生物学特性,掌握,T,细胞发育过程,熟悉,T,细胞表面主要膜分子及其作用,了解,TCRT,细胞和,TCRT,细胞的异同点,掌握TCR分型与结构,45,T,淋巴细胞对抗原的识别及免疫应答,一、,T,细胞对抗原的识别,二、,T,细胞活化的过程,三、,效应性,T,细胞的应答效应,T淋巴细胞对抗原的识别及免疫应答 一、T细胞对抗原的识,46,免疫应答的基本过程,抗原识别,抗原受体与抗原的特异性结合,免疫应答,抗原识别、反应、效应的全过程,免疫反应,免疫效应物质与抗原结合的过程,免疫应答的基本过程 抗原识别 抗原受体与抗原的特异性结合,47,一、,T,细胞对抗原的识别,T,细胞抗原受体及其识别抗原的特点,只识别表达于,APC,表面并与,MHC,分子结合,成复合物的多肽,只识别氨基酸一级序列的多肽线性决定簇,TCR,识别抗原受到,MHC,的限制,CD4,+,T,只识别与,MHC-II,分子结合的肽段,CD8,+,T,只识别与,MHC-I,分子结合的肽段,一、T细胞对抗原的识别T 细胞抗原受体及其识别抗原的特,48,T,细胞与,APC,间的相互作用,T细胞与APC间的相互作用,49,（一）,T,细胞与,APC,的非特异性结合,（一）T细胞与APC的非特异性结合,50,T,细胞与,APC,的非特异性结合,T细胞与APC的非特异性结合,51,（二）,T,细胞与,APC,的特异性结合,（二）T细胞与APC的特异性结合,52,TCR,与,APC,的特异性稳定结合,TCR与APC的特异性稳定结合,53,（三）,T,细胞和,APC,表面共刺激分子的结合,CD28/B7,、,LFA-1/ICAM-1,、,CD2/CD58,等,（三）T细胞和APC表面共刺激分子的结合CD28/B7、LF,54,（四）免疫突触（,immunological synapse,）,中心是,TCR,和抗原肽,-MHC,复合物,周围是细胞黏附分子对,“筏”状结构，相互靠拢成簇,（四）免疫突触（immunological synapse）,55,（一）,T,细胞活化的第一信号,二、,T,细胞活化的信号要求,（一）T细胞活化的第一信号二、T细胞活化的信号要求,56,CD4,+,T,细胞的双识别,CD4+T细胞的双识别,57,（二）,T,细胞激活的第二信号,CD28/B7,LFA-1/ICAM-1,或,ICAM-2,CD2/LFA-3,CD40/CD40L,等,（二）T细胞激活的第二信号CD28/B7,58,T,细胞活化的双信号,T细胞活化的双信号,59,CD28/B7,促进,IL-2,基因转录、合成,缺乏时，,T,细胞,失能（,anergy,）,CTLA4,与,CD28,高同源性，与,B7,亲和力比,CD28,高,20,倍，结合后启动抑制信号，有效制约特异性,T,细胞克隆的过度增殖,CD28/B7促进IL-2基因转录、合成,60,（三）细胞因子促进,T,细胞充分活化,IL-1,、,IL-2,、,IL-6,、,IL-12,等细胞因子,（三）细胞因子促进T细胞充分活化IL-1、IL-2、IL-6,61,三、,T,淋巴细胞活化信号的转导过程,抗原作用下跨膜分子及信号转导成分的多聚化,多聚作用,（,multimerization,）,:,TCR/CD3,、辅助受体,CD4,或,CD8,、,CD45,等相互靠拢成簇（,clustering,）,三、T淋巴细胞活化信号的转导过程抗原作用下跨膜分子及信号转导,62,免疫受体酪氨酸激活基序,（,immunoreceptor tyrosine-based activation motif,ITAM,）,D/Exx YxxL/V x(711) YxxL/V ,Y,：酪氨酸,L,：亮氨酸,V,：缬氨酸,D,：天冬氨酸,E,：谷氨酸,免疫受体酪氨酸激活基序D/Exx YxxL/V x(7,63,T,细胞活化的信号传导,T细胞活化的信号传导,64,四、转录因子活化及基因表达,（一）转录因子活化,AP-1 (Fos,、,Jun),NF-,B,Oct-1,NFAT (nuclear factor of activated T cell ),四、转录因子活化及基因表达（一）转录因子活化AP-1 (Fo,65,迟发型超敏反应性T细胞（TDTH）,glucocorticoid-induced TNFR,原T细胞（pro-T）、前T细胞（pre-T）,This model emphasizes distinct pathways leading to mature Th17 effector cells or Foxp3+ adaptive Tregs (aTreg), induced by a common requirement for TGF-b but differential effects of IL-6 and IL-23.,二、T淋巴细胞亚群,Human IL-17 and IL-17R key features,活化诱导的细胞死亡（activation induced cell death, AICD）,LFA-1/ICAM-1或ICAM-2,一、T细胞对抗原的识别,活化CD8T、NK细胞，增强杀伤活性,2）特异性杀伤功能（CTL、Th1、T）,Through the production of IL-10 and TGF-b they convert immature DC into tolerizing APC,without a requirement for IL-23, IL-1, or IL-18.,（二）T细胞与APC的特异性结合,TDTH 主要为CD4 + Th1,缺乏时，T细胞失能（anergy）,CD4T细胞的增殖分化,contact-dependent manner either (a) directly or (b) indirectly via the APC.,1）根据TCR种类 T、T细胞,Development and function of naturally occurring CD4+CD25+ FoxP3+ regulatory T cells (nTregs).,TCRT和TCRT细胞,（二）,T,细胞基因表达,细胞因子基因,细胞因子受体基因,黏附分子基因,MHC,迟发型超敏反应性T细胞（TDTH）（二）T细胞基因表达细胞因,66,（三）,T,细胞克隆性增殖和分化,CD4,T,细胞的增殖分化,CD8,T,细胞的增殖分化,（三）T细胞克隆性增殖和分化CD4T细胞的增殖分化,67,五、效应,T,细胞的作用,Th0,细胞,Th2,细胞介导,体液免疫,Th1,细胞介导,细胞免疫,IL-12,IL-4,五、效应T细胞的作用Th0细胞Th2细胞介导体液免疫Th,68,诱导迟发型超敏反应，活化招募,M,在炎症局部浸润,活化增强,APC,表达,MHC,分子或其他粘附分子表达,活化,CD8,T,、,NK,细胞，增强杀伤活性,1.,Th1,型,CD4,T,细胞的作用,诱导迟发型超敏反应，活化招募M在炎症局部浸润1. Th1型,69,T,H,1,细胞免疫应答的效应阶段,T,H,1,IL-2,IFN-,TNF-,GM-CSF,IL-3,等,巨噬细胞、中性粒,细胞等活化、聚集、,局部浸润,迟发型 超敏反应,巨噬细胞活化增强,MHC-II,和粘附分子,表达,更有效的,APC,形成,激活,巨噬细胞,NK,细胞,Tc,细胞,T,H,细胞,更有效的发挥,细胞免疫功能,记忆性,T,H,TH1细胞免疫应答的效应阶段TH1IL-2巨噬细胞、中性粒迟,70,Th1,细胞激活巨噬细胞的机制,Th1细胞激活巨噬细胞的机制,71,Th1,细胞所产生的细胞因子及其生物学作用,Th1细胞所产生的细胞因子及其生物学作用,72,调节,M,（,招募、抑制：,IL-10/FasL/TGF-,）,活化,B,细胞，诱导,Ig,类型转换,2.,Th,2,型,CD4,T,细胞的作用,调节M（招募、抑制：IL-10/FasL/TGF-）2.,73,Th2,型,CD4,+,T,细胞与,B,细胞,Th2型CD4+ T细胞与B细胞,74,坏死、凋亡、非溶解性途径,Activation Induced Cell Death,3.,CD,8,细胞,毒性,T,细胞的作用,坏死、凋亡、非溶解性途径3. CD8细胞毒性T细胞的作用,75,CD8,+,CTL,胞毒效应示意图,CD8+CTL胞毒效应示意图,76,释放颗粒物质,穿孔素（,perforin,）,颗粒酶,激活,caspase 10,释放,TNF,启动凋亡信