[精品课件]适应性免疫应答细胞T淋巴细胞

1、INSTITUTE FOR IMMUNOBIOLOGYInstitute for ImmunobiologyDepartment of ImmunologyCenter for Gene Immunization and Vaccine ResearchFudan UniversityShanghai, ChinaT淋巴细胞淋巴细胞 一、一、T淋巴细胞的外表分子及其作用淋巴细胞的外表分子及其作用 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

2、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作用一、一、T淋巴细胞外表分子淋巴细胞外表分子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CD3Gamma DeltaEpsilon Zeta Et

3、a 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细胞等细胞等外表；外表；是是HIV受体，与受体，与APC外表外表MHC-II分子非多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细胞外表，与细胞外表，与APC外表外表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，又能参或靶细胞的相互作用，又能参与抗原刺激与抗原刺激TCR-CD3分子信号转导分子信号转导

4、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号主要是CD28-CD80/86，CTLA4-CD80/86给予已活化T细胞抑制信号。CD40LTAPCCD28CD80/86CTLA4CD40LFA1ICAM1LFA2LFA

5、31、CD28和和CTLA-4(intercellular adhesion molecule-1) T细胞与APC细胞间的主要辅助分子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细胞分化发育细胞分化发育thymic corpuscle 胸腺微环境是诱导并调控胸腺微环境是诱导并调控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-TTCR 、CD3 、CD4 、C

6、D8 双阳性期双阳性期DPTCR 、CD3low、CD4 、CD8 单阳性期单阳性期SPTCR 、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节的功能1. T细胞发育的阳性选择细胞发育的阳性选择positive selectionCD4+CD8+T细胞胸腺基质细胞外表MHC分子如果与MHC-I结合，最终分化为CD8+T细胞如果与MHC-II结合那么最终分化为CD4+T细胞如果与MHC分子不结合那么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

7、时具有别抗原时具有MHC限制性限制性2. T细胞发育的阴性选择细胞发育的阴性选择negative selection其TCR识别胸腺基质细胞外表高亲和力的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去除自身反响性经阴性选择可去除自身反响性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

8、，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

9、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功能功能 Th细胞细胞 根据所分泌的细胞因子不同，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T细胞和记忆性T细胞 记忆性T细胞表达

10、CD45RO，而初始T细胞表达CD45RA5NK1.1 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 1免疫调节功能Th1、 Th2 、 Th3、Ts 、 Treg2特异性杀伤功能CTL、Th1、T3介导超敏反响TDTH4) 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

11、) 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) mechanismglucocorticoid-induced TNFRfamily related gene (GITR)CD8+ Treg cellsNKT regul

12、atory T cellsMultiple subsets of Treg cellsNaturally 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 naturallyinto nTregs upon beneficial TCR engagement by sel

13、f-peptideMHC complexes and Foxp3 induction in the thymus. Upon instruction in the thymus, nTregs emigrate into the periphery asfunctionally 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

14、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 turn down the response of conventional T cellson her partExtrathymic induction and function of adaptive regulatory T cells. Adaptive regulatory T c

15、ells (aTregs) differentiate from naive conventional CD4+ T cells either as a result of suboptimal antigenic stimulation by resting/immature DC, theinfluence of suppressive cytokines like IL-10, TGF-b or cell contact-dependent interaction with activated nTregs (infectious tolerance). Their mode of ac

16、tion 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 APCFig. 3 Role of Tregs in early and late stages of microbial infections. In the stages of an immune res

17、ponse 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.b At

18、 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 ofmemory T cells

19、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 tra

20、nsientdepletion 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 diminishchronic pathological immune responsesGeneration

21、 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 immune cells to secrete crucial cytokines for T-cell differentiation. Nave CD4+ T cells can be differentiated into diff

22、erent 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 blo

23、cks 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 derived from the thymus can cross-react with some antigens expressed by cancer cells, thus promoting their expa

24、nsion and accumulation in the tumor microenvironment.T-helper-cell differentiationHuman IL-17 and IL-17R key featuresa Two isoforms (long and short). Therapeutic targets for autoimmune inflammatory diseases are associated preferentially with the IL-23/Th17 pathway The pathogenic role for IL-23, not

25、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 both IL-23 and IL-12 (Il12p40/) failed to develop disease af

26、ter 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 and Th17 effector cells (see main body of text for de

27、tails). 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 cytokines, IFNg and IL-4, respectively, potently inhibit

28、 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-c

29、ell 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 cytokines involved in specification of ea

30、ch 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 lines

31、 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 (aTreg), induced by a common requirement for TG

32、F-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

33、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 , TCR stimulation by antigen can induce Th17 cytokine production

34、 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. CD4辅助性T细胞 CD8杀伤性T细胞细胞因子对Th1和Th2细胞的调节作用3. 抑制性T细胞4. 迟发型超敏反响性T细胞TDTHT细胞 掌握掌握TCR分型与结构分型与结构

35、 掌握掌握T细胞分群及不同亚群的生物学特性细胞分群及不同亚群的生物学特性 掌握掌握T细胞发育过程细胞发育过程 熟悉熟悉T细胞外表主要膜分子及其作用细胞外表主要膜分子及其作用 了解了解TCRT细胞和细胞和TCRT细胞的异同点细胞的异同点T淋巴细胞对抗原的识别及免疫应答淋巴细胞对抗原的识别及免疫应答 一、一、T细胞对抗原的识别细胞对抗原的识别 二、二、T细胞活化的过程细胞活化的过程 三、三、效应性效应性T细胞的应答效应细胞的应答效应 免疫应答的根本过程免疫应答的根本过程 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、反响、效应的全过程免疫反响 免疫效应物质与抗原结合的过程 一、一、T细胞

36、对抗原的识别细胞对抗原的识别T 细胞抗原受体及其识别抗原的特点细胞抗原受体及其识别抗原的特点l 只识别表达于只识别表达于APC外表并与外表并与MHC分子结合分子结合 l 成复合物的多肽成复合物的多肽l 只识别氨基酸一级序列的多肽线性决定簇只识别氨基酸一级序列的多肽线性决定簇l TCR识别抗原受到识别抗原受到MHC的限制的限制 CD4+T只识别与只识别与MHC-II分子结合的肽段分子结合的肽段 CD8+T只识别与只识别与MHC-I分子结合的肽段分子结合的肽段T细胞与APC间的相互作用 一一T细胞与细胞与APC的非特异性结合的非特异性结合T细胞与APC的非特异性结合 二二T细胞与细胞与APC的特异

37、性结合的特异性结合TCR与APC的特异性稳定结合 三三T细胞和细胞和APC外表共刺激分子的结合外表共刺激分子的结合CD28/B7、LFA-1/ICAM-1、CD2/CD58等等四免疫突触四免疫突触immunological synapse中心是中心是TCR和抗原肽和抗原肽-MHC复合物复合物周围是细胞黏附分子对周围是细胞黏附分子对“筏状结构，相互靠拢成簇筏状结构，相互靠拢成簇一一T细胞活化的第一信号细胞活化的第一信号二、二、T细胞活化的信号要求细胞活化的信号要求CD4+T细胞的双识别二二T细胞激活的第二信号细胞激活的第二信号CD28/B7LFA-1/ICAM-1或或ICAM-2CD2/LFA-

38、3CD40/CD40L等等T细胞活化的双信号 CD28/B7促进促进IL-2基因转录、合成基因转录、合成缺乏时，缺乏时，T细胞失能细胞失能anergyCTLA4与与CD28高同源性，与高同源性，与B7亲和力比亲和力比CD28高高20倍，结合后启动抑制信号，有效制约特异性倍，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细胞克隆的过度增殖三细胞因子促进三细胞因子促进T细胞充分活化细胞充分活化IL-1、IL-2、IL-6、IL-12等细胞因子等细胞因子三、三、T淋巴细胞活化信号的转导过程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抗原作用下跨膜分子及信号转导成分的多聚

39、化多聚作用多聚作用multimerization:TCR/CD3、辅助受体、辅助受体CD4或或CD8、CD45等相互靠拢成簇等相互靠拢成簇clustering免疫受体酪氨酸激活基序免疫受体酪氨酸激活基序immunoreceptor tyrosine-based activation motif, ITAMD/Exx YxxL/V x(711) YxxL/V Y：酪氨酸：酪氨酸L：亮氨酸：亮氨酸V：缬氨酸：缬氨酸D：天冬氨酸：天冬氨酸E：谷氨酸：谷氨酸T T细细胞胞活活化化的的信信号号传传导导四、转录因子活化及基因表达四、转录因子活化及基因表达一转录因子活化一转录因子活化AP-1 (Fos、Jun)NF-BOct-1NFAT (nuclear factor of activated T cell )二二T细胞基因表达细胞基因表达n细胞因子基因细胞因子基因n细胞因子受体基因细胞因子受体基因n黏附分子基因黏附分子基因nMHC精品精品PPT课件课件 浏览免费浏览免费 下载后可以编辑修改。下载后可以编辑修改。同表寒肺热感冒，是风寒客于肌表，热邪壅肺所致的表寒里热证候。 表寒肺热感冒，或因肺热内蕴、复感风寒，或因表寒未解、入里化热、肺热为表寒所遏而形成。 表寒肺热感冒，多以恶寒发热、咳嗽气喘、痰黄粘稠、烦躁为主症。 表寒肺热感冒因风寒客表，邪热壅肺