醫(yī)學(xué)免疫學(xué)：09 T淋巴細(xì)胞及細(xì)胞免疫

1、DEPARTMENT OF IMMUNOLOGYT淋巴細(xì)胞(T lymphocyte)T淋巴細(xì)胞概述T淋巴細(xì)胞的分化發(fā)育T淋巴細(xì)胞的表面分子及其作用T淋巴細(xì)胞亞群T淋巴細(xì)胞的功能主要內(nèi)容T細(xì)胞 (T lymphocyte)淋巴細(xì)胞概述T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T細(xì)胞。成熟T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(dòng)脈的周圍。T細(xì)胞執(zhí)行特異性細(xì)胞免疫應(yīng)答并在TD-Ag誘導(dǎo)的體液免疫應(yīng)答中發(fā)揮重要作用淋巴細(xì)胞概述基本概念成年人骨髓每天約產(chǎn)生109個(gè)淋巴細(xì)胞成年人體內(nèi)約1012個(gè)淋巴細(xì)胞，童貞細(xì)胞壽命約57周，效應(yīng)細(xì)胞 ：幾天90存

2、在于外周淋巴器官或組織中外周血循環(huán)中淋巴細(xì)胞約占白細(xì)胞總數(shù)的2045T細(xì)胞占60，B細(xì)胞30，NK細(xì)胞10T細(xì)胞在免疫器官中的比例：淋巴液90，胸腺85，淋巴結(jié)75，脾臟35基本數(shù)據(jù)淋巴細(xì)胞的顯著特征：異質(zhì)性（heterogeneity）發(fā)育過(guò)程涉及復(fù)雜的：發(fā)育生物學(xué)（developmental biology）研究方法：表型鑒定、各種動(dòng)物模型建立基本特性T淋巴細(xì)胞的分化發(fā)育T細(xì)胞在胸腺的發(fā)育T細(xì)胞在外周淋巴器官中的分化發(fā)育T細(xì)胞受體(TCR)的發(fā)育T細(xì)胞發(fā)育過(guò)程中的陽(yáng)性選擇T細(xì)胞發(fā)育過(guò)程中的陰性選擇thymic corpuscle T細(xì)胞在胸腺發(fā)育胸腺微環(huán)境是誘導(dǎo)并調(diào)控T細(xì)胞分化發(fā)育的關(guān)鍵因

3、素 胸腺基質(zhì)細(xì)胞（TSC） 細(xì)胞因子 胸腺激素T細(xì)胞在胸腺發(fā)育TCR的發(fā)育DN: b鏈基因開(kāi)始重排 前細(xì)胞替代a鏈pTapTa:b受體表達(dá)于preT表面preT增殖活躍分化為DP細(xì)胞IL-7pTa:b表達(dá)下調(diào)細(xì)胞停止增殖a鏈基因重排開(kāi)始表達(dá)有功能的TCR雙陰性期（DN） 原T細(xì)胞（pro-T）、前T細(xì)胞（pre-T）TCR 、CD3 /low 、CD4 、CD8 雙陽(yáng)性期（DP）TCR 、CD3low、CD4 、CD8 單陽(yáng)性期（SP）TCR 、CD3 、CD4 TCR 、CD3 、CD8 成熟T細(xì)胞，具有識(shí)別抗原、介導(dǎo)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(yáng)性選擇（positive

4、selection）CD4+CD8+T細(xì)胞胸腺基質(zhì)細(xì)胞（表面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)合則最終分化為CD4+T細(xì)胞如果與MHC分子不結(jié)合則在胸腺皮質(zhì)中凋亡胸腺細(xì)胞經(jīng)陽(yáng)性選擇賦予成熟T細(xì)胞在識(shí)別抗原時(shí)具有MHC限制性2. T細(xì)胞發(fā)育的陰性選擇（negative selection）其TCR識(shí)別胸腺基質(zhì)細(xì)胞表面高親和力的MHC或MHC-自身抗原肽的T細(xì)胞克隆將發(fā)生凋亡經(jīng)陰性選擇可清除自身反應(yīng)性T細(xì)胞克隆獲中樞耐受DP或經(jīng)陽(yáng)性選擇的SP的T細(xì)胞T細(xì)胞在胸腺中的陽(yáng)性選擇和陰性選擇 T細(xì)胞在外周淋巴器官中的分化發(fā)育初始細(xì)胞細(xì)胞亞群調(diào)節(jié)性細(xì)胞記憶細(xì)胞T淋

5、巴細(xì)胞表面分子及其作用T細(xì)胞表面受體 T細(xì)胞表面抗原 粘附分子T細(xì)胞表面標(biāo)志MHC抗原 所有T細(xì)胞表達(dá)MHC-I 活化T細(xì)胞表達(dá)MHC-II類分化抗原（CD , cluster of differentiation） 與T細(xì)胞識(shí)別和激活有關(guān)：CD3、CD4、CD8、CD2、CD28家族、CD40L、CD45等T細(xì)胞表面抗原TCR-CD3 complexTCR-CD3復(fù)合物是T細(xì)胞抗原受體與一組CD3（Gamma DeltaEpsilon Zeta Eta ）分子以非共價(jià)鍵結(jié)合而形成的復(fù)合物，是T細(xì)胞識(shí)別抗原和轉(zhuǎn)導(dǎo)信號(hào)的主要單位。TCR特異識(shí)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

6、第一信號(hào)CD3 是T細(xì)胞所特有的表面標(biāo)志 與 TCR以鹽橋形式組成 TCR-CD3復(fù)合體TCR-CD3 復(fù)合體結(jié)構(gòu)模式圖 轉(zhuǎn)導(dǎo)T細(xì)胞活化的第一信號(hào) 功能穩(wěn)定TCR的結(jié)構(gòu)負(fù)責(zé)抗原特異性信號(hào)傳導(dǎo)參與T細(xì)胞發(fā)育CD4/CD8CD4：胸腺細(xì)胞、成熟TH細(xì)胞 巨噬細(xì)胞、DC等 CD8：胸腺細(xì)胞、成熟TC 細(xì)胞 NK細(xì)胞、T等表達(dá)CD4 結(jié)構(gòu)單鏈跨膜糖蛋白分子，胞外區(qū)含有4個(gè)Ig樣結(jié)構(gòu)域分別為D1、D2、D3和D4CD4分子D1結(jié)構(gòu)域可與HIV gp120結(jié)合，是HIV病毒的受體CD4分子的D4結(jié)構(gòu)域能與IL-16結(jié)合，有可能為IL-16受體 IL-16: 刺激CD4T細(xì)胞、單核細(xì)胞及嗜酸性粒細(xì)胞的移行，

7、抑制HIV感染的T細(xì)胞CD4分子結(jié)構(gòu)示意圖lckCD4和CD8共受體分子模式圖 CD8結(jié)構(gòu) 或鏈以二硫鍵連接的二聚體，每條鏈具有一個(gè)IgV樣結(jié)構(gòu)域V樣區(qū)與胞膜之間：富含脯氨酸、絲氨酸和蘇氨酸的連接肽，廣泛糖基化，保護(hù)多肽鏈免于蛋白酶的裂解CD4通過(guò)D1結(jié)構(gòu)域側(cè)面與MHC-II類2結(jié)構(gòu)域結(jié)合CD8通過(guò)鏈V樣結(jié)構(gòu)域與MHC-I類3結(jié)構(gòu)域結(jié)合穩(wěn)定T細(xì)胞與APC或靶細(xì)胞間的結(jié)合CD4和CD8通過(guò)胞漿區(qū)的CxCP基序與p56lck酪氨酸激酶相連，參與T細(xì)胞活化和增殖信號(hào)轉(zhuǎn)導(dǎo) 功能CD4與MHCII結(jié)合位點(diǎn)CD28-B7分子家族 CD28家族成員包括： CD28 CTLA-4 （cytotoxic T l

8、ymphocyte antigen-4） ICOS（inducible T-cell co-stimulator） PD-1（ programmed death 1） CD28家族分子配體均為B7家族分子 均屬于IgSF B7家族成員包括：B7-1（CD80）B7-2（CD86）ICOSLPD-L1、PD-L2 CD28B7分子家族 同源二聚體胞外區(qū)單一IgSF V樣結(jié)構(gòu)域，具有高度保守的MYPPY基序胞漿區(qū)可與多種信號(hào)分子和激酶作用胞漿區(qū)SH3-激酶結(jié)合位點(diǎn)（PYAP），對(duì)細(xì)胞分化和IL-2的產(chǎn)生重要 CD28 CD28家族分子結(jié)構(gòu)與CD28有31同源性，生物進(jìn)化十分保守與B7分子結(jié)合必需的

9、MYPPY基序CTLA-4與B7結(jié)合的親和力明顯高于CD28胞漿區(qū)有ITIM（immunoreceptor tyrosine-based inhibition motif）基序，與SHP-2蛋白酪氨酸磷酸酶的SH2結(jié)構(gòu)域結(jié)合，募集并活化PTP，阻斷由PTK參與的活化信號(hào)轉(zhuǎn)導(dǎo)通路 CTLA-4 （cytotoxic T lymphocyte antigen-4）分布和功能 CD28分布：組成性表達(dá)所有CD4T細(xì)胞和50CD8T細(xì)胞功能：1)與B7結(jié)合提供共刺激信號(hào)，促進(jìn)T細(xì)胞活化2)轉(zhuǎn)導(dǎo)信號(hào)與TCR轉(zhuǎn)導(dǎo)信號(hào)起協(xié)同促進(jìn)作用，顯著減低有效活化T細(xì)胞所需的TCR數(shù)量 分布：初始T細(xì)胞不表達(dá)，活化后快速

10、上調(diào)表達(dá)與B7結(jié)合親和力高功能：轉(zhuǎn)導(dǎo)負(fù)調(diào)節(jié)信號(hào)，在調(diào)節(jié)外周T細(xì)胞耐受中發(fā)揮重要作用 體內(nèi)阻斷CTLA-4能增強(qiáng)抗腫瘤免疫，加劇自身免疫應(yīng)答 CTLA-4CD28/CTLA-4B7-1/B7-2結(jié)合 ICOS（inducible T-cell co-stimulator）氨基酸水平：與CD28有39同源性胞外區(qū)有與ICOSL結(jié)合的FDPPPF基序胞漿區(qū)特殊基序，可與PI-3K的p85亞單位結(jié)合ICOS 區(qū)別CD28和ICOS分子及其功能的結(jié)構(gòu)基礎(chǔ)CD28有SH3-激酶結(jié)合位點(diǎn)（PYAP）ICOS缺乏此位點(diǎn)，NATURE REVIEWS，VOLUME 2 | FEBRUARY 2002 | 125

11、ICOS T細(xì)胞活化后快速誘導(dǎo)表達(dá)表達(dá)水平受到TCR和CD28信號(hào)的影響Th1，Th2分化早期，ICOS均上調(diào)表達(dá)生發(fā)中心中Th細(xì)胞高表達(dá)ICOS ICOS與CD28所產(chǎn)生的共刺激信號(hào)具有協(xié)同促進(jìn)作用 ICOS主要調(diào)節(jié)已活化的或效應(yīng)T細(xì)胞產(chǎn)生細(xì)胞因子增加多種細(xì)胞因子分泌不增加CTL的殺傷功能 ICOS對(duì)Th2分泌IL-4和IL-13發(fā)揮重要作用 ICOS上調(diào)Th2表達(dá)CD40L，可影響B(tài)細(xì)胞Ig類別轉(zhuǎn)化在初始T細(xì)胞活化過(guò)程中阻斷ICOS，能促進(jìn)Th1的分化程序性死亡分子-1(programmed death -1, PD-1)無(wú)MYPPPY基序，有半胱氨酸殘基，易形成二硫鍵而組成同源二聚體胞漿

12、區(qū)含有2個(gè)酪氨酸，其中一個(gè)參與組成ITIMPD-1L和PD-2L為B7家族新成員，被確定為PD-1的配體 PD-1 PD-1 分布：表達(dá)于：活化T細(xì)胞、NK、B和髓系細(xì)胞表面功能：抑制T細(xì)胞增殖 主要機(jī)制：拮抗CD28-B7信號(hào)途徑，抑制生長(zhǎng)因子的分泌 CD2 CD2又稱為淋巴細(xì)胞功能相關(guān)抗原-2（lymphocyte function associated antigen 2, LFA-2） 與其配體LFA-3 ( CD58 ) 結(jié)合CD2分布：胸腺細(xì)胞、 T細(xì)胞和NK細(xì)胞CD58分布：廣泛，T細(xì)胞、APC、粒細(xì)胞、紅細(xì)胞和血小板表面，某些上皮細(xì)胞、內(nèi)皮細(xì)胞和成纖維細(xì)胞也可表達(dá)CD2和CD5

13、8分子結(jié)構(gòu)相似，胞外區(qū)N端 ：IgSF V樣區(qū)，近膜段：IgSF C2樣區(qū) CD2/CD58功能 增強(qiáng)T細(xì)胞與APC或靶細(xì)胞的粘附作用 促進(jìn)T細(xì)胞識(shí)別抗原及其介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)p59fyn 胸腺細(xì)胞的分化成熟CD40L（CD154） 結(jié)構(gòu)屬于TNF超家族成員II型膜蛋白分子，C端在胞外區(qū)，N端在胞內(nèi)區(qū) 以三聚體形式結(jié)合三聚體的CD40 分布活化的T細(xì)胞表面（主要CD4+T/部分CD8+T和 T）活化的B細(xì)胞、嗜堿性粒細(xì)胞、NK細(xì)胞、單核細(xì)胞等LFA-1/ICAM-1功能 介導(dǎo)T細(xì)胞與APC或靶細(xì)胞的粘附作用T細(xì)胞與APC細(xì)胞間的主要輔助分子4. 其它一些受體 絲裂原受體 細(xì)胞因子受體 病毒受體1）

14、初始T細(xì)胞、效應(yīng)T細(xì)胞和記憶性T細(xì)胞 初始T細(xì)胞表達(dá)CD45RA,CD62Lhigh ， 效應(yīng)T細(xì)胞表達(dá)IL-2R,整合素,CD44,CD45RO 記憶性T細(xì)胞表達(dá)CD45RO,黏附分子(整合素,CD44) NK1.1 T細(xì)胞 其TCR識(shí)別的抗原是由CD1分子提呈的脂類和糖脂類抗原三、T細(xì)胞亞群三、T細(xì)胞亞群2）根據(jù)TCR種類 T、T細(xì)胞在末梢血主要為T細(xì)胞可占95%，而T細(xì)胞只占1%10%。T細(xì)胞為主要參予免疫應(yīng)答的T細(xì)胞，兩者特性和功能均不相同。TCRT和TCRT細(xì)胞 TCR 分布 表型識(shí)別抗原MHC限制功能TCRT TCRT 極大多樣性60-70,外周淋巴組織成熟CD2CD3CD4/CD

15、8817aa經(jīng)典MHCTh、Tc較少多樣性5-15,粘膜上皮成熟大多數(shù)CD2CD3簡(jiǎn)單多肽、 HSP、脂類、多糖MHC樣分子Tc3）根據(jù)T細(xì)胞是否表達(dá)CD4或CD8分類 CD4+ T細(xì)胞或CD8+ T細(xì)胞TCRTCD4+細(xì)胞：CD2+、CD3+、CD4+、CD8-TCR識(shí)別抗原是MHC類分子限制性 TH0、Th1和Th2、行使Tc、Ts功能TCRTCD8+細(xì)胞：CD2+、CD3+、CD4-、CD8+TCR識(shí)別抗原是MHCI類分子限制性 行使Tc、Ts功能Th細(xì)胞 根據(jù)所分泌的細(xì)胞因子不同，將其分為Th1、Th2和Th17亞型。 Th3、I型調(diào)節(jié)性T細(xì)胞(Tr1)Tc細(xì)胞 殺傷、分泌IFN、IL

16、-4、IL-5和IL-10Treg4）功能性亞群：Th、Tc(CTL)、Treg初始T細(xì)胞效應(yīng)T細(xì)胞記憶T細(xì)胞T細(xì)胞活化階段abT細(xì)胞gdT細(xì)胞Th細(xì)胞CTL(Tc)Treg細(xì)胞CD8T+細(xì)胞CD4T+細(xì)胞TCR類型CD4/8功能Th1Th2Th17TregGeneration and conversion of Treg cells in the tumor microenvironmentTumor cells not only provide antigenic stimulation for T cell activation but also interact with tumor-

17、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 milie

18、u. 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 intoTh17 cells. Alternatively, naturally occurring CD

19、4+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.T-helper-cell differentiationHuman IL-17 and IL-17R key featuresa Two isoforms (long and short). Therapeutic

20、 targets for autoimmune inflammatory diseases are associated preferentially 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. Com

21、pared 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.Model of Th1 versus Th17 lineage development from naive CD4 T

22、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.Antagonistic cytokine networks control CD4 effect

23、or T-cell differentiationRecent 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 throu

24、gh 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).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(jiǎn)圖Although functional CD4 T cell development has been dominated by the Th1-Th2 paradigm for nearly two decades, the num

25、ber 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 li

26、neage 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 LineagesModel of Branching Th17 and Adaptive Treg Lineage Deve

27、lopmentThis 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

28、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 I

29、L-1, which can act synergistically with IL-23 to induce Th17 cytokineproductionindependently 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

30、by which cytokine products of Th17 (IL-6) or aTreg cells (TGF-b1) may reinforce lineage development. CD4輔助性T細(xì)胞的功能 CD8殺傷性T細(xì)胞的功能調(diào)節(jié)性T細(xì)胞的功能四、T細(xì)胞功能細(xì)胞因子對(duì)Th1和Th2細(xì)胞的調(diào)節(jié)作用Naturally occurring CD4+CD25+ Treg cells (56%) GITR and Foxp3 a cellcell contact mechanismAntigen-induced Tr1 and Th3 cells (IL-10) and/or

31、(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 regulatory T c

32、ellsMultiple 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 self-peptide

33、MHC 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 cells in

34、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 cells (aTr

35、egs) 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 action invo

36、lves 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 response aga

37、inst 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 the late

38、 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 cellsTreg-base

39、d 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 transientdep

40、letion 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 responses掌握TCR分型與結(jié)構(gòu)掌握T細(xì)胞發(fā)育過(guò)程

41、掌握T細(xì)胞分群及不同亞群的生物學(xué)特性熟悉T細(xì)胞表面主要膜分子及其作用了解TCRT細(xì)胞和TCRT細(xì)胞的異同點(diǎn)教學(xué)要求T淋巴細(xì)胞對(duì)抗原的識(shí)別及免疫應(yīng)答 一、T細(xì)胞對(duì)抗原的識(shí)別 二、T細(xì)胞活化的過(guò)程 三、效應(yīng)性T細(xì)胞的應(yīng)答效應(yīng) 免疫應(yīng)答的基本過(guò)程 抗原識(shí)別 抗原受體與抗原的特異性結(jié)合免疫應(yīng)答 抗原識(shí)別、反應(yīng)、效應(yīng)的全過(guò)程免疫反應(yīng) 免疫效應(yīng)物質(zhì)與抗原結(jié)合的過(guò)程 一、T細(xì)胞對(duì)抗原的識(shí)別T 細(xì)胞抗原受體及其識(shí)別抗原的特點(diǎn) 只識(shí)別表達(dá)于APC表面并與MHC分子結(jié)合 成復(fù)合物的多肽 只識(shí)別氨基酸一級(jí)序列的多肽線性決定簇 TCR識(shí)別抗原受到MHC的限制 CD4+T只識(shí)別與MHC-II分子結(jié)合的肽段 CD8+T只

42、識(shí)別與MHC-I分子結(jié)合的肽段T細(xì)胞與APC間的相互作用 （一）T細(xì)胞與APC的非特異性結(jié)合T細(xì)胞與APC的非特異性結(jié)合 （二）T細(xì)胞與APC的特異性結(jié)合TCR與APC的特異性穩(wěn)定結(jié)合 （三）T細(xì)胞和APC表面共刺激分子的結(jié)合CD28/B7、LFA-1/ICAM-1、CD2/CD58等（四）免疫突觸（immunological synapse）中心是TCR和抗原肽-MHC復(fù)合物周圍是細(xì)胞黏附分子對(duì)“筏”狀結(jié)構(gòu)，相互靠攏成簇（一）T細(xì)胞活化的第一信號(hào)二、T細(xì)胞活化的信號(hào)要求CD4+T細(xì)胞的雙識(shí)別（二）T細(xì)胞激活的第二信號(hào)CD28/B7LFA-1/ICAM-1或ICAM-2CD2/LFA-3CD40/CD40L等T細(xì)胞活化的雙信號(hào) CD28/B7促進(jìn)IL-2基因轉(zhuǎn)錄、合成缺乏時(shí)，T細(xì)胞失能（anergy）CTLA4與CD28高同源性，與B7親和力比CD28高20倍，結(jié)合后啟動(dòng)抑制信號(hào)，有效制約特異性T細(xì)胞克隆的過(guò)度增殖（三）細(xì)