[精品課件]適應(yīng)性免疫應(yīng)答細(xì)胞T淋巴細(xì)胞

1、INSTITUTE FOR IMMUNOBIOLOGYInstitute for ImmunobiologyDepartment of ImmunologyCenter for Gene Immunization and Vaccine ResearchFudan UniversityShanghai, ChinaT淋巴細(xì)胞淋巴細(xì)胞 一、一、T淋巴細(xì)胞的外表分子及其作用淋巴細(xì)胞的外表分子及其作用 二、二、T淋巴細(xì)胞亞群淋巴細(xì)胞亞群 三、三、T淋巴細(xì)胞功能淋巴細(xì)胞功能T細(xì)胞是由一群功能不同的異質(zhì)性淋巴細(xì)胞組成，細(xì)胞是由一群功能不同的異質(zhì)性淋巴細(xì)胞組成，由于它在胸腺內(nèi)分化成熟故稱為由于它在胸腺內(nèi)分

2、化成熟故稱為T細(xì)胞。細(xì)胞。成熟成熟T細(xì)胞由胸腺遷出，移居于周圍淋巴組織中細(xì)胞由胸腺遷出，移居于周圍淋巴組織中淋巴節(jié)的副皮質(zhì)區(qū)和脾白髓小動脈的周圍。淋巴節(jié)的副皮質(zhì)區(qū)和脾白髓小動脈的周圍。T細(xì)胞執(zhí)行特異性細(xì)胞免疫應(yīng)答細(xì)胞執(zhí)行特異性細(xì)胞免疫應(yīng)答并在并在TD-Ag誘導(dǎo)的體液免疫應(yīng)答中發(fā)揮重要作用誘導(dǎo)的體液免疫應(yīng)答中發(fā)揮重要作用一、一、T淋巴細(xì)胞外表分子淋巴細(xì)胞外表分子TCRCD3復(fù)合物復(fù)合物TCR可分為TCR和TCR兩種類型結(jié)構(gòu)相似兩條異源二聚體肽鏈藉二硫鍵組成的跨膜分子每條肽鏈含V、C區(qū)，類似Ig結(jié)構(gòu)TCR-CD3復(fù)合物是T細(xì)胞抗原受體與一組CD3Gamma DeltaEpsilon Zeta Et

3、a 分子以非共價鍵結(jié)合而形成的復(fù)合物，是T細(xì)胞識別抗原和轉(zhuǎn)導(dǎo)信號的主要單位。TCR特異識別由MHC分子提呈的抗原肽，CD3分子轉(zhuǎn)導(dǎo)T細(xì)胞活化的第一信號CD4 主要分布于成熟主要分布于成熟Th細(xì)胞、巨噬細(xì)胞、細(xì)胞、巨噬細(xì)胞、DC細(xì)胞等細(xì)胞等外表；外表；是是HIV受體，與受體，與APC外表外表MHC-II分子非多態(tài)區(qū)結(jié)合分子非多態(tài)區(qū)結(jié)合CD8 主要分布于成熟主要分布于成熟Tc細(xì)胞外表，與細(xì)胞外表，與APC外表外表MHC-I分子分子非多態(tài)區(qū)結(jié)合非多態(tài)區(qū)結(jié)合既能加強既能加強T細(xì)胞與細(xì)胞與APC或靶細(xì)胞的相互作用，又能參或靶細(xì)胞的相互作用，又能參與抗原刺激與抗原刺激TCR-CD3分子信號轉(zhuǎn)導(dǎo)分子信號轉(zhuǎn)導(dǎo)

4、2. CD4和和CD8分子分子加強T細(xì)胞與APC或靶細(xì)胞的相互作用通過胞漿區(qū)的CxCP基序與p56lck(Src family tyrosine kinase LCK)酪氨酸激酶相連，參與T細(xì)胞活化和增殖信號轉(zhuǎn)導(dǎo) CD4和和CD8 T細(xì)胞輔助受體3. 協(xié)同輔助信號分子協(xié)同輔助信號分子協(xié)同信號分子TCR-CD3復(fù)合分子可提供第1信號協(xié)同刺激信號(costimulatouy signal)或第2信號參與T細(xì)胞活化的協(xié)同刺激信號主要是CD28-CD80/86，CTLA4-CD80/86給予已活化T細(xì)胞抑制信號。CD40LTAPCCD28CD80/86CTLA4CD40LFA1ICAM1LFA2LFA

5、31、CD28和和CTLA-4(intercellular adhesion molecule-1) T細(xì)胞與APC細(xì)胞間的主要輔助分子2、ICOS3、CD40L4、CD25、LFA-1和和ICAM-14. 其它一些受體其它一些受體 絲裂原受體 細(xì)胞因子受體 病毒受體二、二、T細(xì)胞分化發(fā)育細(xì)胞分化發(fā)育thymic corpuscle 胸腺微環(huán)境是誘導(dǎo)并調(diào)控胸腺微環(huán)境是誘導(dǎo)并調(diào)控T細(xì)細(xì)胞分化發(fā)育的關(guān)鍵因素胞分化發(fā)育的關(guān)鍵因素 胸腺基質(zhì)細(xì)胞胸腺基質(zhì)細(xì)胞TSC 細(xì)胞因子細(xì)胞因子 胸腺激素胸腺激素雙陰性期雙陰性期DN 原原T細(xì)胞細(xì)胞pro-T、前、前T細(xì)胞細(xì)胞pre-TTCR 、CD3 、CD4 、C

6、D8 雙陽性期雙陽性期DPTCR 、CD3low、CD4 、CD8 單陽性期單陽性期SPTCR 、CD3 、CD4 TCR 、CD3 、CD8 成熟成熟T細(xì)胞，具有識別抗原、介導(dǎo)細(xì)胞，具有識別抗原、介導(dǎo)免疫應(yīng)答及參與免疫調(diào)節(jié)的功能免疫應(yīng)答及參與免疫調(diào)節(jié)的功能1. T細(xì)胞發(fā)育的陽性選擇細(xì)胞發(fā)育的陽性選擇positive selectionCD4+CD8+T細(xì)胞胸腺基質(zhì)細(xì)胞外表MHC分子如果與MHC-I結(jié)合，最終分化為CD8+T細(xì)胞如果與MHC-II結(jié)合那么最終分化為CD4+T細(xì)胞如果與MHC分子不結(jié)合那么在胸腺皮質(zhì)中凋亡胸腺細(xì)胞經(jīng)陽性選擇賦予成熟胸腺細(xì)胞經(jīng)陽性選擇賦予成熟T細(xì)胞在識細(xì)胞在識別抗原

7、時具有別抗原時具有MHC限制性限制性2. T細(xì)胞發(fā)育的陰性選擇細(xì)胞發(fā)育的陰性選擇negative selection其TCR識別胸腺基質(zhì)細(xì)胞外表高親和力的MHC或MHC-自身抗原肽的T細(xì)胞克隆將發(fā)生凋亡經(jīng)陰性選擇可去除自身反響性經(jīng)陰性選擇可去除自身反響性T細(xì)胞克隆細(xì)胞克隆獲中樞耐受獲中樞耐受DP或經(jīng)陽性選擇的SP的T細(xì)胞T細(xì)胞在胸腺中的陽性選擇和陰性選擇 三、三、T細(xì)胞亞群細(xì)胞亞群1根據(jù)根據(jù)TCR種類種類 T、T細(xì)胞細(xì)胞在末梢血主要為在末梢血主要為T細(xì)胞可占細(xì)胞可占95%，而，而T細(xì)胞細(xì)胞只占只占1%10%。T細(xì)胞為主要參予免疫應(yīng)答細(xì)胞為主要參予免疫應(yīng)答的的T細(xì)胞，兩者特性和功能均不相同。細(xì)胞

8、，兩者特性和功能均不相同。TCRT和和TCRT細(xì)胞細(xì)胞 TCR 分布分布 表型表型識別抗原識別抗原MHC限制限制功能功能TCRT TCRT 極大多樣性極大多樣性60-70,外周淋巴組織外周淋巴組織成熟成熟CD2CD3CD4/CD8817aa經(jīng)典經(jīng)典MHCTh、Tc較少多樣性較少多樣性5-15,粘膜上皮粘膜上皮成熟大多數(shù)成熟大多數(shù)CD2CD3簡單多肽、簡單多肽、 HSP、脂類、多糖、脂類、多糖MHC樣分子樣分子Tc2根據(jù)根據(jù)T細(xì)胞是否表達(dá)細(xì)胞是否表達(dá)CD4或或CD8分類分類 CD4+ T細(xì)胞或細(xì)胞或CD8+ T細(xì)胞細(xì)胞TCRTCD4+細(xì)胞：細(xì)胞：CD2+、CD3+、CD4+、CD8-TCR識別抗

9、原是識別抗原是MHC類分子限制性類分子限制性 TH0、Th1和和Th2、行使、行使Tc、Ts功能功能TCRTCD8+細(xì)胞：細(xì)胞：CD2+、CD3+、CD4-、CD8+TCR識別抗原是識別抗原是MHCI類分子限制性類分子限制性 行使行使Tc、Ts功能功能 Th細(xì)胞細(xì)胞 根據(jù)所分泌的細(xì)胞因子不同，根據(jù)所分泌的細(xì)胞因子不同，將其分為將其分為Th0、Th1和和Th2亞型。亞型。 Tc細(xì)胞細(xì)胞 殺傷、分泌殺傷、分泌IFN、IL-4、IL-5和和IL-10 Ts細(xì)胞細(xì)胞 TDTH 主要為主要為CD4 + Th13功能性亞群：功能性亞群：Th、Tc、TDTH、Ts4初始T細(xì)胞和記憶性T細(xì)胞 記憶性T細(xì)胞表達(dá)

10、CD45RO，而初始T細(xì)胞表達(dá)CD45RA5NK1.1 T細(xì)胞 其TCR識別的抗原是由CD1分子提呈的脂類和糖脂類抗原Leukocyte Common antigen 1免疫調(diào)節(jié)功能Th1、 Th2 、 Th3、Ts 、 Treg2特異性殺傷功能CTL、Th1、T3介導(dǎo)超敏反響TDTH4) 新型效應(yīng)細(xì)胞：Th17四、四、T細(xì)胞功能細(xì)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細(xì)胞分化和免疫調(diào)節(jié)細(xì)胞因子網(wǎng)絡(luò)模式簡圖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輔助性T細(xì)胞 CD8殺傷性T細(xì)胞細(xì)胞因子對Th1和Th2細(xì)胞的調(diào)節(jié)作用3. 抑制性T細(xì)胞4. 遲發(fā)型超敏反響性T細(xì)胞TDTHT細(xì)胞 掌握掌握TCR分型與結(jié)構(gòu)分型與結(jié)構(gòu)

35、 掌握掌握T細(xì)胞分群及不同亞群的生物學(xué)特性細(xì)胞分群及不同亞群的生物學(xué)特性 掌握掌握T細(xì)胞發(fā)育過程細(xì)胞發(fā)育過程 熟悉熟悉T細(xì)胞外表主要膜分子及其作用細(xì)胞外表主要膜分子及其作用 了解了解TCRT細(xì)胞和細(xì)胞和TCRT細(xì)胞的異同點細(xì)胞的異同點T淋巴細(xì)胞對抗原的識別及免疫應(yīng)答淋巴細(xì)胞對抗原的識別及免疫應(yīng)答 一、一、T細(xì)胞對抗原的識別細(xì)胞對抗原的識別 二、二、T細(xì)胞活化的過程細(xì)胞活化的過程 三、三、效應(yīng)性效應(yīng)性T細(xì)胞的應(yīng)答效應(yīng)細(xì)胞的應(yīng)答效應(yīng) 免疫應(yīng)答的根本過程免疫應(yīng)答的根本過程 抗原識別 抗原受體與抗原的特異性結(jié)合免疫應(yīng)答 抗原識別、反響、效應(yīng)的全過程免疫反響 免疫效應(yīng)物質(zhì)與抗原結(jié)合的過程 一、一、T細(xì)胞

36、對抗原的識別細(xì)胞對抗原的識別T 細(xì)胞抗原受體及其識別抗原的特點細(xì)胞抗原受體及其識別抗原的特點l 只識別表達(dá)于只識別表達(dá)于APC外表并與外表并與MHC分子結(jié)合分子結(jié)合 l 成復(fù)合物的多肽成復(fù)合物的多肽l 只識別氨基酸一級序列的多肽線性決定簇只識別氨基酸一級序列的多肽線性決定簇l TCR識別抗原受到識別抗原受到MHC的限制的限制 CD4+T只識別與只識別與MHC-II分子結(jié)合的肽段分子結(jié)合的肽段 CD8+T只識別與只識別與MHC-I分子結(jié)合的肽段分子結(jié)合的肽段T細(xì)胞與APC間的相互作用 一一T細(xì)胞與細(xì)胞與APC的非特異性結(jié)合的非特異性結(jié)合T細(xì)胞與APC的非特異性結(jié)合 二二T細(xì)胞與細(xì)胞與APC的特異

37、性結(jié)合的特異性結(jié)合TCR與APC的特異性穩(wěn)定結(jié)合 三三T細(xì)胞和細(xì)胞和APC外表共刺激分子的結(jié)合外表共刺激分子的結(jié)合CD28/B7、LFA-1/ICAM-1、CD2/CD58等等四免疫突觸四免疫突觸immunological synapse中心是中心是TCR和抗原肽和抗原肽-MHC復(fù)合物復(fù)合物周圍是細(xì)胞黏附分子對周圍是細(xì)胞黏附分子對“筏狀結(jié)構(gòu)，相互靠攏成簇筏狀結(jié)構(gòu)，相互靠攏成簇一一T細(xì)胞活化的第一信號細(xì)胞活化的第一信號二、二、T細(xì)胞活化的信號要求細(xì)胞活化的信號要求CD4+T細(xì)胞的雙識別二二T細(xì)胞激活的第二信號細(xì)胞激活的第二信號CD28/B7LFA-1/ICAM-1或或ICAM-2CD2/LFA-

38、3CD40/CD40L等等T細(xì)胞活化的雙信號 CD28/B7促進(jìn)促進(jìn)IL-2基因轉(zhuǎn)錄、合成基因轉(zhuǎn)錄、合成缺乏時，缺乏時，T細(xì)胞失能細(xì)胞失能anergyCTLA4與與CD28高同源性，與高同源性，與B7親和力比親和力比CD28高高20倍，結(jié)合后啟動抑制信號，有效制約特異性倍，結(jié)合后啟動抑制信號，有效制約特異性T細(xì)胞克隆的過度增殖細(xì)胞克隆的過度增殖三細(xì)胞因子促進(jìn)三細(xì)胞因子促進(jìn)T細(xì)胞充分活化細(xì)胞充分活化IL-1、IL-2、IL-6、IL-12等細(xì)胞因子等細(xì)胞因子三、三、T淋巴細(xì)胞活化信號的轉(zhuǎn)導(dǎo)過程淋巴細(xì)胞活化信號的轉(zhuǎn)導(dǎo)過程抗原作用下跨膜分子及信號轉(zhuǎn)導(dǎo)成分的多聚化抗原作用下跨膜分子及信號轉(zhuǎn)導(dǎo)成分的多聚

39、化多聚作用多聚作用multimerization:TCR/CD3、輔助受體、輔助受體CD4或或CD8、CD45等相互靠攏成簇等相互靠攏成簇clustering免疫受體酪氨酸激活基序免疫受體酪氨酸激活基序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：纈氨酸：纈氨酸D：天冬氨酸：天冬氨酸E：谷氨酸：谷氨酸T T細(xì)細(xì)胞胞活活化化的的信信號號傳傳導(dǎo)導(dǎo)四、轉(zhuǎn)錄因子活化及基因表達(dá)四、轉(zhuǎn)錄因子活化及基因表達(dá)一轉(zhuǎn)錄因子活化一轉(zhuǎn)錄因子活化AP-1 (Fos、Jun)NF-BOct-1NFAT (nuclear factor of activated T cell )二二T細(xì)胞基因表達(dá)細(xì)胞基因表達(dá)n細(xì)胞因子基因細(xì)胞因子基因n細(xì)胞因子受體基因細(xì)胞因子受體基因n黏附分子基因黏附分子基因nMHC精品精品PPT課件課件 瀏覽免費瀏覽免費 下載后可以編輯修改。下載后可以編輯修改。同表寒肺熱感冒，是風(fēng)寒客于肌表，熱邪壅肺所致的表寒里熱證候。 表寒肺熱感冒，或因肺熱內(nèi)蘊、復(fù)感風(fēng)寒，或因表寒未解、入里化熱、肺熱為表寒所遏而形成。 表寒肺熱感冒，多以惡寒發(fā)熱、咳嗽氣喘、痰黃粘稠、煩躁為主癥。 表寒肺熱感冒因風(fēng)寒客表，邪熱壅肺