[精品課件]適應性免疫應答細胞T淋巴細胞

1、INSTITUTE FOR IMMUNOBIOLOGYInstitute for ImmunobiologyDepartment of ImmunologyCenter for Gene Immunization and Vaccine ResearchFudan UniversityShanghai, ChinaT淋巴細胞淋巴細胞 一、一、T淋巴細胞的外表分子及其作用淋巴細胞的外表分子及其作用 二、二、T淋巴細胞亞群淋巴細胞亞群 三、三、T淋巴細胞功能淋巴細胞功能T細胞是由一群功能不同的異質(zhì)性淋巴細胞組成，細胞是由一群功能不同的異質(zhì)性淋巴細胞組成，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細胞。細胞。成熟成熟T細胞由胸腺遷出，移居于周圍淋巴組織中細胞由胸腺遷出，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細胞執(zhí)行特異性細胞免疫應答細胞執(zhí)行特異性細胞免疫應答并在并在TD-Ag誘導的體液免疫應答中發(fā)揮重要作用誘導的體液免疫應答中發(fā)揮重要作用一、一、T淋巴細胞外表分子淋巴細胞外表分子TCRCD3復合物復合物TCR可分為TCR和TCR兩種類型結構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結構TCR-CD3復合物是T細胞抗原受體與一組CD3Gamma DeltaEpsilon Zeta Et

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

4、2. CD4和和CD8分子分子加強T細胞與APC或靶細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細胞活化和增殖信號轉(zhuǎn)導 CD4和和CD8 T細胞輔助受體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細胞抑制信號。CD40LTAPCCD28CD80/86CTLA4CD40LFA1ICAM1LFA2LFA

5、31、CD28和和CTLA-4(intercellular adhesion molecule-1) T細胞與APC細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 細胞因子受體 病毒受體二、二、T細胞分化發(fā)育細胞分化發(fā)育thymic corpuscle 胸腺微環(huán)境是誘導并調(diào)控胸腺微環(huán)境是誘導并調(diào)控T細細胞分化發(fā)育的關鍵因素胞分化發(fā)育的關鍵因素 胸腺基質(zhì)細胞胸腺基質(zhì)細胞TSC 細胞因子細胞因子 胸腺激素胸腺激素雙陰性期雙陰性期DN 原原T細胞細胞pro-T、前、前T細胞細胞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細胞，具有識別抗原、介導細胞，具有識別抗原、介導免疫應答及參與免疫調(diào)節(jié)的功能免疫應答及參與免疫調(diào)節(jié)的功能1. T細胞發(fā)育的陽性選擇細胞發(fā)育的陽性選擇positive selectionCD4+CD8+T細胞胸腺基質(zhì)細胞外表MHC分子如果與MHC-I結合，最終分化為CD8+T細胞如果與MHC-II結合那么最終分化為CD4+T細胞如果與MHC分子不結合那么在胸腺皮質(zhì)中凋亡胸腺細胞經(jīng)陽性選擇賦予成熟胸腺細胞經(jīng)陽性選擇賦予成熟T細胞在識細胞在識別抗原

7、時具有別抗原時具有MHC限制性限制性2. T細胞發(fā)育的陰性選擇細胞發(fā)育的陰性選擇negative selection其TCR識別胸腺基質(zhì)細胞外表高親和力的MHC或MHC-自身抗原肽的T細胞克隆將發(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細胞克隆細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細胞T細胞在胸腺中的陽性選擇和陰性選擇 三、三、T細胞亞群細胞亞群1根據(jù)根據(jù)TCR種類種類 T、T細胞細胞在末梢血主要為在末梢血主要為T細胞可占細胞可占95%，而，而T細胞細胞只占只占1%10%。T細胞為主要參予免疫應答細胞為主要參予免疫應答的的T細胞，兩者特性和功能均不相同。細胞

8、，兩者特性和功能均不相同。TCRT和和TCRT細胞細胞 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細胞是否表達細胞是否表達CD4或或CD8分類分類 CD4+ T細胞或細胞或CD8+ T細胞細胞TCRTCD4+細胞：細胞：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+細胞：細胞：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細胞細胞 根據(jù)所分泌的細胞因子不同，根據(jù)所分泌的細胞因子不同，將其分為將其分為Th0、Th1和和Th2亞型。亞型。 Tc細胞細胞 殺傷、分泌殺傷、分泌IFN、IL-4、IL-5和和IL-10 Ts細胞細胞 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細胞和記憶性T細胞 記憶性T細胞表達

10、CD45RO，而初始T細胞表達CD45RA5NK1.1 T細胞 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介導超敏反響TDTH4) 新型效應細胞：Th17四、四、T細胞功能細胞功能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細胞分化和免疫調(diào)節(jié)細胞因子網(wǎng)絡模式簡圖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細胞 CD8殺傷性T細胞細胞因子對Th1和Th2細胞的調(diào)節(jié)作用3. 抑制性T細胞4. 遲發(fā)型超敏反響性T細胞TDTHT細胞 掌握掌握TCR分型與結構分型與結構

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

36、對抗原的識別細胞對抗原的識別T 細胞抗原受體及其識別抗原的特點細胞抗原受體及其識別抗原的特點l 只識別表達于只識別表達于APC外表并與外表并與MHC分子結合分子結合 l 成復合物的多肽成復合物的多肽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分子結合的肽段分子結合的肽段 CD8+T只識別與只識別與MHC-I分子結合的肽段分子結合的肽段T細胞與APC間的相互作用 一一T細胞與細胞與APC的非特異性結合的非特異性結合T細胞與APC的非特異性結合 二二T細胞與細胞與APC的特異

37、性結合的特異性結合TCR與APC的特異性穩(wěn)定結合 三三T細胞和細胞和APC外表共刺激分子的結合外表共刺激分子的結合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復合物復合物周圍是細胞黏附分子對周圍是細胞黏附分子對“筏狀結構，相互靠攏成簇筏狀結構，相互靠攏成簇一一T細胞活化的第一信號細胞活化的第一信號二、二、T細胞活化的信號要求細胞活化的信號要求CD4+T細胞的雙識別二二T細胞激活的第二信號細胞激活的第二信號CD28/B7LFA-1/ICAM-1或或ICAM-2CD2/LFA-

38、3CD40/CD40L等等T細胞活化的雙信號 CD28/B7促進促進IL-2基因轉(zhuǎn)錄、合成基因轉(zhuǎn)錄、合成缺乏時，缺乏時，T細胞失能細胞失能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，結合后啟動抑制信號，有效制約特異性倍，結合后啟動抑制信號，有效制約特異性T細胞克隆的過度增殖細胞克隆的過度增殖三細胞因子促進三細胞因子促進T細胞充分活化細胞充分活化IL-1、IL-2、IL-6、IL-12等細胞因子等細胞因子三、三、T淋巴細胞活化信號的轉(zhuǎn)導過程淋巴細胞活化信號的轉(zhuǎn)導過程抗原作用下跨膜分子及信號轉(zhuǎn)導成分的多聚化抗原作用下跨膜分子及信號轉(zhuǎn)導成分的多聚

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細細胞胞活活化化的的信信號號傳傳導導四、轉(zhuǎn)錄因子活化及基因表達四、轉(zhuǎn)錄因子活化及基因表達一轉(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細胞基因表達細胞基因表達n細胞因子基因細胞因子基因n細胞因子受體基因細胞因子受體基因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、復感風寒，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。 表寒肺熱感冒因風寒客表，邪熱壅肺