1、T淋巴细胞淋巴细胞 一、一、T淋巴细胞的表面分子及其作用淋巴细胞的表面分子及其作用 二、二、T淋巴细胞亚群淋巴细胞亚群 三、三、T淋巴细胞功能淋巴细胞功能T细胞是由一群功能不同的异质性淋巴细胞组成，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由于它在胸腺内分化成熟故称为T细胞。细胞。成熟成熟T细胞由胸腺迁出，移居于周围淋巴组织中细胞由胸腺迁出，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。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细胞执行特异性细胞免疫应答并在并在TD-Ag诱导的体液免疫应答中发挥重要作用诱导的体液免疫应答中发挥重要
2、作用一、一、T淋巴细胞表面分子淋巴细胞表面分子1.TCRCD3复合物复合物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TCR-CD3复合物是T细胞抗原受体与一组CD3（Gamma DeltaEpsilon 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CD4 主要分布于成熟主要分布于成熟Th细胞、巨噬细胞、细胞、巨噬细胞、DC细胞等表面；细胞等表面；是是HIV受体，与受体，与APC表面表面MHC-II分子非多
3、态区结合分子非多态区结合CD8 主要分布于成熟主要分布于成熟Tc细胞表面，与细胞表面，与APC表面表面MHC-I分子分子非多态区结合非多态区结合既能加强既能加强T细胞与细胞与APC或靶细胞的相互作用，又能参与抗原或靶细胞的相互作用，又能参与抗原刺激刺激TCR-CD3分子信号转导分子信号转导2.CD4和和CD8分子分子加强T细胞与APC或靶细胞的相互作用通过胞浆区的CxCP基序与p56lck(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和和CD8 T细胞辅助受体Antigen-induced Tr1 and Th3 cells
4、 (IL-10)and/or(TGF-b)IL-23 signaling induces responsiveness to IL-18 and IL-1,which can act synergistically with IL-23 to induce Th17 cytokineproductionAlternatively,TCR stimulation by antigen can induce Th17 cytokine production directly,掌握T细胞活化的条件MHC-II和粘附分子加强T细胞与APC或靶细胞的相互作用诱导迟发型超敏反应，活化招募M在炎症局部浸润加
5、强T细胞与APC或靶细胞的相互作用免疫受体酪氨酸激活基序IL-1、IL-2、IL-6、IL-12等细胞因子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.协同刺激信号(costimulatouy signal)或第2信号differentiated into different subsets of CD4+T cells,inc
6、luding Th1,Th2,Treg and IL-17-producing T cells(Th17),depending upon the strength of antigen stimulation and cytokine milieu.Development and function of naturally occurring CD4+CD25+FoxP3+regulatory T cells(nTregs).In addition:nTregs may(c)condition DC to become tolerogenic and turn down the respons
7、e of conventional T cellsTregs respond to the stimulation by mature DC and proliferate.Alternatively,TCR stimulation by antigen can induce Th17 cytokine production directly,诱导迟发型超敏反应，活化招募M在炎症局部浸润CD8细胞毒性T细胞的作用3.协同（辅助）信号分子协同（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
8、号主要是CD28-CD80/86，CTLA4-CD80/86给予已活化T细胞抑制信号。CD40LTAPCCD28CD80/86CTLA4CD40LFA1ICAM1LFA2LFA31、CD28和和CTLA-4(intercellular adhesion molecule-1)T细胞与APC细胞间的主要辅助分子CD28/B7、LFA-1/ICAM-1、CD2/CD58等Studies by Cua and co-workers have demonstrated that disease development requires IL-23,but not IL-12,in EAE and CI
9、A.（三）细胞因子促进T细胞充分活化三、T淋巴细胞功能Alternatively,TCR stimulation by antigen can induce Th17 cytokine production directly,移植排除反应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).been
10、 identified.Caspase8 激活DNA 内切酶Th17 cells.Therapeutic targets for autoimmune inflammatorySelective 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,trans
11、plantation and pregnancy disorders.两条异源二聚体肽链藉二硫键组成的跨膜分子协同（辅助）信号分子（immunoreceptor tyrosine-based activation motif,ITAM）ck-dependent mechanismIL-23 signaling induces responsiveness to IL-18 and IL-1,which can act synergistically with IL-23 to induce Th17 cytokineproductionModel of Branching Th17 and A
12、daptive Treg Lineage DevelopmentIL-23 signaling induces responsiveness to IL-18 and IL-1,which can act synergistically with IL-23 to induce Th17 cytokineproductionDP或经阳性选择的SP的T细胞Th1细胞所产生的细胞因子及其生物学作用被动细胞死亡（passive cell death,PCD）2、ICOS3、CD40L4、CD25、LFA-1和和ICAM-14.其它一些受体其它一些受体 丝裂原受体 细胞因子受体 病毒受体二、二、T细胞
13、分化发育细胞分化发育thymic corpuscle 胸腺微环境胸腺微环境是诱导并调控是诱导并调控T细细胞分化发育的关键因素胞分化发育的关键因素 胸腺基质细胞（胸腺基质细胞（TSC）细胞因子细胞因子 胸腺激素胸腺激素双阴性期（双阴性期（DN）原原T细胞（细胞（pro-T）、前）、前T细胞（细胞（pre-T）TCR、CD3 、CD4 、CD8 双阳性期（双阳性期（DP）TCR 、CD3low、CD4 、CD8 单阳性期（单阳性期（SP）TCR 、CD3 、CD4 TCR 、CD3 、CD8 成熟成熟T细胞，具有识别抗原、介导细胞，具有识别抗原、介导免疫应答及参与免疫调节的功能免疫应答及参与免疫调
14、节的功能1.T细胞发育的细胞发育的阳性选择阳性选择（positive 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胸腺细胞经阳性选择赋予成熟T细胞在识细胞在识别抗原时具有别抗原时具有MHC限制性限制性2.T细胞发育的细胞发育的阴性选择阴性选择（negative selection）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经阴性选择可清除自
15、身反应性T细胞克隆细胞克隆获中枢耐受获中枢耐受DP或经阳性选择的SP的T细胞T细胞在胸腺中的阳性选择和阴性选择 三、三、T细胞亚群细胞亚群1）根据）根据TCR种类种类 T、T细胞细胞在末梢血主要为在末梢血主要为T细胞可占细胞可占95%，而，而T细胞细胞只占只占1%10%。T细胞为主要参予免疫应答细胞为主要参予免疫应答的的T细胞，两者特性和功能均不相同。细胞，两者特性和功能均不相同。TCRT和和TCRT细胞细胞 TCR 分布分布 表型表型识别抗原识别抗原MHC限制限制功能功能TCRT TCRT 极大多样性极大多样性60-70,外周淋巴组织外周淋巴组织成熟成熟CD2CD3CD4/CD8817aa经
16、典经典MHCTh、Tc较少多样性较少多样性5-15,粘膜上皮粘膜上皮成熟大多数成熟大多数CD2CD3简单多肽、简单多肽、HSP、脂类、多糖、脂类、多糖MHC样分子样分子Tc2）根据）根据T细胞是否表达细胞是否表达CD4或或CD8分类分类 CD4+T细胞或细胞或CD8+T细胞细胞TCRTCD4+细胞：细胞：CD2+、CD3+、CD4+、CD8-TCR识别抗原是识别抗原是MHC类分子限制性类分子限制性 TH0、Th1和和Th2、行使、行使Tc、Ts功能功能TCRTCD8+细胞：细胞：CD2+、CD3+、CD4-、CD8+TCR识别抗原是识别抗原是MHCI类分子限制性类分子限制性 行使行使Tc、Ts
17、功能功能（四）免疫突触（immunological synapse）IL-1、IL-2、IL-6、IL-12等细胞因子functionally fully competent cells.（三）细胞因子促进T细胞充分活化IL-23 signaling induces responsiveness to IL-18 and IL-1,which can act synergistically with IL-23 to induce Th17 cytokineproductionT细胞发育的阳性选择（positive selection）一、T淋巴细胞的表面分子及其作用Th1细胞所产生的细胞因子
18、及其生物学作用a cell contact dependent免疫受体酪氨酸激活基序Tn:naive,postthymic CD4 T cell precursors;Tp:thymic precursors.influence of suppressive cytokines like IL-10,TGF-b or cell contact-dependent interaction with activated nTregs(infectious tolerance).TH1细胞免疫应答的效应阶段Tn:naive,postthymic CD4 T cell precursors;Tp:th
19、ymic precursors.glucocorticoid-induced TNFR（一）T细胞活化的第一信号been identified.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.been identified.Antigen-induced Tr1 and Th3 cells (IL-10)and/or(TGF-b)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。Th细胞细胞 根据所分泌的细
20、胞因子不同，根据所分泌的细胞因子不同，将其分为将其分为Th0、Th1和和Th2亚型。亚型。Tc细胞细胞 杀伤、分泌杀伤、分泌IFN、IL-4、IL-5和和IL-10 Ts细胞细胞 TDTH 主要为主要为CD4+Th13）功能性亚群：）功能性亚群：Th、Tc、TDTH、Ts4）初始初始T细胞和记忆性细胞和记忆性T细胞细胞 记忆性T细胞表达CD45RO，而初始T细胞表达CD45RA5）NK1.1 T细胞细胞 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 1）免疫调节功能（Th1、Th2、Th3、Ts、Treg）2）特异性杀伤功能（CTL、T
21、h1、T）3）介导超敏反应（TDTH）4)新型效应细胞：Th17四、四、T细胞功能细胞功能Naturally occurring CD4+CD25+Treg cells (56%)GITR and Foxp3 a cellcell contact mechanismAntigen-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
22、cell contact dependent or soluble factor-dependent (other than IL-10and/or TGF-b)mechanismglucocorticoid-induced TNFRfamily related gene(GITR)CD8+Treg cellsNKT regulatory T cellsMultiple subsets of Treg cellsNaturally occurring CD4+CD25+Foxp3+Tregs Development and function of naturally occurring CD4
23、+CD25+FoxP3+regulatory T cells(nTregs).Development:bone marrow-derived CD4+T cell precursors develop naturallyinto 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 asfunctionally ful
24、ly 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 acontact-dependent manner either(a)directly or(b)indirectly via the APC.In addition:nTregs may(c)condition DC to become tolerogenic and tur
25、n down the response of conventional T cellson her partExtrathymic 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,theinfluence of s
26、uppressive 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
27、immature DC into tolerizing APCFig.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 c
28、ell-derived IL-2 and microbial components such as TLR-ligands.Tregs respond to the stimulation by mature DC and proliferate.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 r
29、esponse by acting on effector T cells and DC.Possibly,this late activity is also for the proper development ofmemory T cellsTreg-based immune intervention strategies.Selective manipulation of Treg function is an emerging target for immune intervention strategies to either boost responses in cancer a
30、nd microbial diseases or suppress those unwanted in autoimmunity,allergy,transplantation and pregnancy disorders.The transientdepletion 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 vira
31、l infections.On the other hand their selective activation could diminishchronic pathological immune responsesGeneration and conversion of Treg cells in the tumor microenvironmentTumor cells not only provide antigenic stimulation for T cell activation but also interact with tumor-infiltrating innate
32、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 combinati
33、on 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 intoTh17 cells.Alternatively,naturally occurring CD4+CD25+Treg cells directly derive
34、d from the thymus can cross-react with some antigens expressed by cancer cells,thus promoting their expansion and accumulation in the tumor microenvironment.T-helper-cell differentiationHuman IL-17 and IL-17R key featuresa Two isoforms(long and short).Naive CD4 T cells(Tn)activated by antigen presen
35、ted on immature DCs that do not produce IL-6 production are induced by TGF-b to express Foxp3 and develop into aTregs(top panel).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 mi
36、ce deficient for IL-12(Il12p35/)developed more severe disease.independently ofTCRstimulation.在末梢血主要为T细胞可占95%，而T细胞只占1%10%。CD8T细胞的增殖分化活化增强APC表达MHC分子或其他粘附分子表达CD40/CD40L等Antigen-induced Tr1 and Th3 cells (IL-10)and/or(TGF-b)LFA-1/ICAM-1或ICAM-2TCR识别抗原受到MHC的限制胸腺微环境是诱导并调控T细胞分化发育的关键因素FasL与靶细胞Fas死亡结构域协同刺激信号(
37、costimulatouy signal)或第2信号Alternatively,TCR stimulation by antigen can induce Th17 cytokine production directly,4)新型效应细胞：Th17TDTH 主要为CD4+Th1Selective manipulation of Treg function is an emerging target for immune intervention strategies to either boost responses in cancer and microbial diseases or s
38、uppress those unwanted in autoimmunity,allergy,transplantation and pregnancy disorders.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.Model of Branching Th17 and Adaptive Treg Lineage Devel
39、opmentRecent studies have established that Th1 and Th2 effector cytokines,IFNg and IL-4,respectively,potently inhibit Th17 development.CD8+CTL胞毒效应示意图Possibly,this late activity is also for the proper development of Therapeutic targets for autoimmune inflammatory diseases are associated preferentiall
40、y with the IL-23/Th17 pathway The pathogenic role for IL-23,not IL-12,in mouse models of autoimmunityStudies 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 bot
41、h IL-23 and IL-12(Il12p40/)failed to develop disease after antigenic challenge,whereas mice deficient for IL-12(Il12p35/)developed more severe disease.Model of Th1 versus Th17 lineage development from naive CD4 T cell precursors(Tn)This model emphasizes the distinct lineages leading to mature Th1 an
42、d 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.Antagonistic cytokine networks control CD4 effector T-cell differentiationRecent studies have established that Th1 and Th2 effector cytokin
43、es,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
44、through direct effects on naive CD4 T-cell precursors(Tn).CD4+T细胞分化和免疫调节细胞因子网络模式简图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 cytok
45、ines 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 cel
46、l precursors;Tp:thymic precursors.Dotted lines represent less well-defined lineage relationships.Diversification of CD4 T Cell LineagesModel of Branching Th17 and Adaptive Treg Lineage DevelopmentThis model emphasizes distinct pathways leading to mature Th17 effector cells or Foxp3+adaptive Tregs(aT
47、reg),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-activa
48、tedDCsthat 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 cytokineproductionindependently ofTCRstimulation.Alternative
49、ly,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.Antigen-induced Tr1 and Th3
50、cells (IL-10)and/or(TGF-b)without a requirement for IL-23,IL-1,or IL-18.TCRT和TCRT细胞免疫受体酪氨酸激活基序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.FasL与靶细胞Fas死
