T細(xì)胞亞群進(jìn)展及臨床意義

1、醫(yī)學(xué)免疫學(xué)上海第二醫(yī)科大學(xué)免疫教研室1醫(yī)學(xué)免疫學(xué)上海第二醫(yī)科大學(xué)免疫教研室2T T 細(xì)胞亞群與功能細(xì)胞亞群與功能 根據(jù)根據(jù)TCR種類種類 TCR-1（TCR），），TCR-2（TCR ）根據(jù)根據(jù)TCR-2（TCR ）表達(dá)）表達(dá)CD4或或CD8的不同的不同 CD4+T分子表型為分子表型為CD2、CD3、CD4 CD8+T分子表型為分子表型為CD2、CD3、CD8 根據(jù)功能根據(jù)功能 Th、Tc、Ts、TDTH 根據(jù)對(duì)抗原的應(yīng)答不同根據(jù)對(duì)抗原的應(yīng)答不同 初始初始T細(xì)胞、抗原活化過的細(xì)胞、抗原活化過的T細(xì)胞、記憶性細(xì)胞、記憶性T細(xì)胞細(xì)胞T細(xì)胞亞群 CD4 + 、CD8 +亞群 CD4+T細(xì)胞識(shí)別由13

2、17個(gè)氨基酸殘基組成的抗原肽，并受自身的MHC II類限制。CD8 + T細(xì)胞識(shí)別810個(gè)氨基酸組成的抗原肽，并受MHC I類限制。 TCRT細(xì)胞和TCRT細(xì)胞 5 Th、Tc、Ts和TDTH細(xì)胞 Th細(xì)胞 根據(jù)所分泌的細(xì)胞因子不同，將其分為Th0、Th1和Th2亞型。 Tc細(xì)胞 Tc1細(xì)胞主要分泌IFN；Tc2細(xì)胞則主要分泌IL-4、IL-5和IL-10。 Ts細(xì)胞 TDTH 主要為CD4 + Th16TCR 極大多態(tài)性極大多態(tài)性 極少多態(tài)性極少多態(tài)性分布分布 外周血外周血 60-70% 5-15% 組織組織 外周淋巴組織外周淋巴組織 黏膜上皮黏膜上皮表型表型 CD3+CD2+ 100% 1

3、00% CD4+CD8- 60-65% 20-50% CD4-CD8+ 30-35% 20-50% CD4-CD8- 5% 50%識(shí)別抗原識(shí)別抗原 8-17aa 簡(jiǎn)單多肽、簡(jiǎn)單多肽、HSP、脂類、多糖、脂類、多糖MHC限制限制 經(jīng)典經(jīng)典MHC分子分子 MHC類似分子類似分子輔助細(xì)胞輔助細(xì)胞 Th細(xì)胞細(xì)胞殺傷細(xì)胞殺傷細(xì)胞 Tc細(xì)胞細(xì)胞 Tc細(xì)胞細(xì)胞TCRT細(xì)胞抑制性抑制性T細(xì)胞細(xì)胞(Ts) CD4T細(xì)胞細(xì)胞 CD表型：表型：CD3+CD4+CD8-，主要為，主要為Th細(xì)胞亞群細(xì)胞亞群 1.CD41.CD4+ +ThTh細(xì)胞及其功能細(xì)胞及其功能 2. 2. CD8T細(xì)胞細(xì)胞 CD表型表型：CD3+

4、CD8+CD4-，主要為，主要為CTL細(xì)胞亞群細(xì)胞亞群 CD8+殺傷性T細(xì)胞 CTL的主要作用是直接殺傷靶細(xì)胞，有兩種機(jī)制：細(xì)胞裂解和細(xì)胞凋亡11CTL 殺傷靶細(xì)胞的機(jī)制殺傷靶細(xì)胞的機(jī)制12CD8CD8+ +TcTc細(xì)胞（細(xì)胞（CTLCTL）及其功能）及其功能免疫應(yīng)答的主要效應(yīng)細(xì)胞免疫應(yīng)答的主要效應(yīng)細(xì)胞，在腫，在腫瘤免疫和抗病毒免疫中發(fā)揮重要瘤免疫和抗病毒免疫中發(fā)揮重要作用（作用（抗腫瘤抗腫瘤）作用特點(diǎn)：特異直接殺傷靶細(xì)胞，在殺傷過程中自身不受損傷，可反復(fù)連續(xù)殺傷。 作用機(jī)制：作用機(jī)制：細(xì)胞裂解（細(xì)胞裂解（cytolysis） 細(xì)胞凋亡細(xì)胞凋亡 （apoptosis）抗腫瘤Introducti

5、on of Th1/Th2 cellsIn 1986, T.R. Mosman and R.L. Coffman observed that individual clones of mouse helper T cells could be separated into two classes depending upon the specific cytokines the cells secrete in response to antigenic stimulation.Induction of Th1 and Th2 ResponsesTh2Th1AntigensIL-4IL-12I

6、FN-APCNave CD4Effector CellsSignal 2Signal 1IL-2IFN-IL-4IL-5IL-10Cellular Immune ResponsesHumoral Immune ResponsesLeishmania major Infection in Mice Provides a Useful Model to Study Th1 and Th2 Differentiation and Memory in vivoLeishmania major infection: Mouse ModelsBalb/CBalb/CBL/6BL/6Th 1 respons

7、eDeathDeathRecoveryRecoveryTh 2 responseIL-12IL-12/IFN-Signaling of IL-12 Receptor12TYK2JAK2p40p35STAT4PPYStat4Stat4PPYYIFN-ProductionExpression 1: Expressed on Th1, Th2, N.K., and B cells 2: Expressed on activated Nave T, Th1, and N.K. cellsRegulationEnhanced by: activation of -CD28, IL-2, IL-7, IL

8、-15, IFN- (mouse), IFN- (human)Inhibited by: IL-4, IL-10, TGF- , PGE2, DexCytokines On Th1 Cell DevelopmentPathogenAPC CD4+T CellSTAT4TCRIFN-IFN-+IL-27TCCR/WSX-1IL-12IL-12IL-23IL-12IL-18IL-18Nave CD4+Th1Th1 EffectorIL-12R12IL-18RIL-18RIL-12R1IL-12R1IL-12R122STAT1T-betIFN-T-betSTAT4STAT4NFKBGADD45p3B

9、IRAKNFKB如果敲除IL-12基因細(xì)胞免疫功能下降80% T淋巴細(xì)胞的功能(1)介導(dǎo)細(xì)胞免疫應(yīng)答介導(dǎo)細(xì)胞免疫應(yīng)答(2)分泌細(xì)胞因子參與免疫調(diào)節(jié)21Interleukin-9 (IL-9)-producing T cells (Th9 Cells) 肥大細(xì)胞、過敏反應(yīng)IntroductionRecently, two reports described a discrete subset of interleukin-9(IL-9)-producing T cells that might be closely related to the TH2-cell lineage.These IL

10、-9-producing T cells seem to be a distinct population that does not show the characteristics of other described T-cell subsets-“TH9” cells.2425TGF- deviates TH2 cells to a “TH-9” fateIL-9-producing T cells could be generated from TH2 cells that were exposed to TGF- in vitro, even when the TH2 cells

11、were highly polarized.IL-4 inhibits TGF-induced Foxp3+ T cellsIL-4 actively inhibits the induction of Foxp3 in the presence of TGF-.The inhibition of Foxp3 expression by IL-4 is mediated through the IL-4-STAT6 pathway.The Foxp3 can directly interact with GATA-3 and this association inhibits GATA-3 m

12、ediated transactivation of IL-5, which is one of its target genes.TTcTh0Tc2Tc1TregTh2Th1TregCD4+CD8+CD4+25+27效應(yīng)效應(yīng)-調(diào)控調(diào)控 過強(qiáng)和過弱過強(qiáng)和過弱The Role of Suppressor or Regulatory T Cells (Treg) in ImmunityIntroduction Regulation of immune responses to self-antigen is a complex process Maintaining self-tolerance

13、Retaining the capacity to mount immune responses against invading microorganismsDiscovery of Suppressor T Cells In 1995, Sakaguchi et al made the seminal observation: The transfer of CD4+ T cells which had been depleted of the the minor subpopulation (10%) of cells to nu/nu recepients induced organ-

14、specific autoimmune diseases in the majority of recipients. The minor subpopulation of cells are CD4+CD25+ T cells.Discovery of Suppressor T cellsCD4+CD25+ Regulatory T cellsA unique lineage of regulatory T cells capable of maintaining self tolerance in vivo32TCD8CD4CD4+25+Th1Tc2Tc1Th2Th3Tr1Peripher

15、al T lymphocyte5-10%30%Th4?60%Thymus33Overview of phenotypes and functions of CD4+ T cellsNaveCD4Th1TrTh2IFN-Cell mediated immune responsesIL-4 IL-5 IL-10 IL-13humoral immune responseTr 1Th 3CD4+CD25+High IL-10 , low TGF-TGF-cell-cell contactNatural Tr in thymus contact-dependentAdaptive Tr in perip

16、heral lymphoid tissue cytokines-dependant Regulatory T cells CD4+CD25+ Tr cells: Comprise 5-10% of peripheral CD4 T cells in human and mice Produced in thymus as an unique lineage of CD4 T cells Secret IL-10 and/or TGF-, but little IL-2 Anergic and suppressive CD45RBlow, CTLA-4 high35淋巴細(xì)胞及其亞群分析淋巴細(xì)胞及

17、其亞群分析 T淋巴細(xì)胞及亞群： 外周血中成熟淋巴細(xì)胞主要屬于TCRT細(xì)胞，可分為Th、Ts、Treg，TCRT細(xì)胞和NK1.1T細(xì)胞等，他們都有一個(gè)共同的標(biāo)志CD3。36 a、輔助/誘導(dǎo)性T淋巴細(xì)胞（Th）占27-51%，是主要的功能亞群，主要表達(dá)CD3CD4CD8。 b、抑制/細(xì)胞毒性T淋巴細(xì)胞（Ts）占15-44%，是主要的效應(yīng)性T細(xì)胞亞群，主要表達(dá)CD3CD4 CD8。 c、Treg細(xì)胞是近年來新發(fā)現(xiàn)的一個(gè)T淋巴細(xì)胞亞群，具有重要的免疫調(diào)節(jié)功能，在自身免疫病、腫瘤和器官移植排斥反應(yīng)中具有重要作用，主要標(biāo)志為CD4CD25FoxP3。37 d、Th /Ts比例，一般采用CD4 /CD8比例

18、，正常值2：1，免疫力低下時(shí)比例倒置。 e、T淋巴細(xì)胞的絕對(duì)計(jì)數(shù)，在某些疾病中T淋巴細(xì)胞會(huì)大量減少；CD4和CD8T細(xì)胞均減少。 f、T淋巴細(xì)胞活化；CD69正常情況下極少表達(dá)，早期出現(xiàn)CD69表達(dá)，中期CD69、CD25（IL-2R）表達(dá)，晚期出現(xiàn)CD71（轉(zhuǎn)鐵蛋白受體）和HLA-DR表達(dá)。 g、初始T細(xì)胞和記憶T細(xì)胞亞群表達(dá)見157；38 B細(xì)胞及亞群；B細(xì)胞在外周血占5%-15%，與自身免疫疾病、B細(xì)胞系的腫瘤關(guān)系密切；B慢性淋巴細(xì)胞白血病與淋巴瘤等主要表達(dá)CD19、20、21、22。 NK細(xì)胞：外周血占10%，CD16、CD56是特異性標(biāo)志。NK細(xì)胞在抗感染、抗腫瘤和移植排斥反應(yīng)中具有

19、重要作用。 DC:是重要的抗原提呈細(xì)胞分為髓樣CD1淋巴樣CD2。重要標(biāo)志CD11c+、HLA-DR+。39臨床意義 總T和總B及其亞群的意義 總T（50-84%）和總B（5-18%）可以用來判斷某些免疫缺陷和自身免疫性疾病。對(duì)CD4和CD8T細(xì)胞的測(cè)定有助于免疫缺陷疾病、自身免疫性疾病、移植排斥反應(yīng)的監(jiān)測(cè)。 CD4 /CD8的意義 評(píng)價(jià)自身免疫失調(diào)、免疫失調(diào)或免疫缺陷病病人的免疫狀態(tài)，監(jiān)測(cè)骨髓移植病人以免受到急性GVHD的攻擊。（自免病比值升高，病毒感染、腫瘤、再障比值降低）。 NK細(xì)胞的意義 NK（7-40%）細(xì)胞能夠介導(dǎo)對(duì)某些腫瘤細(xì)胞和病毒感染細(xì)胞的細(xì)胞毒性作用。40抑制性抑制性T細(xì)胞細(xì)

20、胞(Ts) 2. 2. CD8T細(xì)胞細(xì)胞 CD表型表型：CD3+CD8+CD4-，主要為，主要為CTL細(xì)胞亞群細(xì)胞亞群 TGF- deviates TH2 cells to a “TH-9” fateIL-9-producing T cells could be generated from TH2 cells that were exposed to TGF- in vitro, even when the TH2 cells were highly polarized.IL-4 inhibits TGF-induced Foxp3+ T cellsIL-4 actively inhibits the induction of Foxp3 in the presence of TGF-.The inhibition of Foxp3 expression by IL-4 is mediated through the IL-4-STAT6 pathway.The Foxp3 can directly interact with GATA-3 and this association inhibits GATA-