t細(xì)胞亞群進(jìn)展及臨床意義

1、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,,2,,,,醫(yī)學(xué)免疫學(xué),上海第二醫(yī)科大學(xué)免疫教研室,,3,,T 細(xì)胞亞群與功能,根據(jù)TCR種類—— TCR-1（TCR??），TCR-2（TCR ??）,根據(jù)TCR-2（TCR ??）表達(dá)CD4或CD8的不同— CD4+T——分子表型為CD2、CD3、CD4 CD8+T——分子表型為CD2、CD3、CD8,根據(jù)功能—— Th、

2、Tc、Ts、TDTH,根據(jù)對(duì)抗原的應(yīng)答不同—— 初始T細(xì)胞、抗原活化過的T細(xì)胞、記憶性T細(xì)胞,T細(xì)胞亞群,CD4 + 、CD8 +亞群 CD4+T細(xì)胞識(shí)別由13~17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8~10個(gè)氨基酸組成的抗原肽，并受MHC I類限制。TCRαβT細(xì)胞和TCRγδT細(xì)胞,6,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、Th

3、1和Th2亞型。Tc細(xì)胞 Tc1細(xì)胞主要分泌IFNγ；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 + Th1,7,（一）TCR?? T細(xì)胞 和 TCR?? T細(xì)胞,TCR 極大多態(tài)性 極少多態(tài)性分布 外周血 60-70%

4、 5-15% 組織 外周淋巴組織 黏膜上皮表型 CD3+CD2+ 100% 100% CD4+CD8- 60-65% 20-50% C

5、D4-CD8+ 30-35% 20-50% CD4-CD8- <5% ≥50%識(shí)別抗原 8-17aa 簡(jiǎn)單多肽、HSP、脂類、多糖MHC限制

6、 經(jīng)典MHC分子 MHC類似分子輔助細(xì)胞 Th細(xì)胞殺傷細(xì)胞 Tc細(xì)胞 Tc細(xì)胞,特性 TCR ?? T細(xì)胞,,,,TCRγδT細(xì)胞,按CD分子不同,按功能不同,αβT細(xì)胞,CD4＋T細(xì)胞,C

7、D8＋T細(xì)胞,輔助性T細(xì)胞(Th),細(xì)胞毒性T細(xì)胞(CTL或Tc),抑制性T細(xì)胞(Ts),,,,,CD4＋T細(xì)胞 CD表型：CD3+CD4+CD8-，主要為Th細(xì)胞亞群,,識(shí)別抗原時(shí)受MHC-Ⅱ類分子限制 通過分泌細(xì)胞因子發(fā)揮效應(yīng)功能 CD4＋T細(xì)胞(部分)也具有細(xì)胞殺傷功能,,作用特點(diǎn),,1.CD4+

8、Th細(xì)胞及其功能,2. CD8＋T細(xì)胞 CD表型：CD3+CD8+CD4-，主要為CTL細(xì)胞亞群,,識(shí)別抗原時(shí)受MHC- Ⅰ類分子限制 免疫調(diào)節(jié)作用, 如釋放IFN-γ、TNF-α和TNF-β等細(xì)胞因子 具有細(xì)胞殺傷功能,,作用特點(diǎn),,CD8+殺傷性T細(xì)胞 CTL的主要作用是直接

9、殺傷靶細(xì)胞，有兩種機(jī)制：細(xì)胞裂解和細(xì)胞凋亡,12,13,CD8+Tc細(xì)胞（CTL）及其功能,免疫應(yīng)答的主要效應(yīng)細(xì)胞，在腫瘤免疫和抗病毒免疫中發(fā)揮重要作用（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：細(xì)胞裂解（cytolysis） 細(xì)胞凋亡 （apoptosis）,

10、,,抗腫瘤,Introduction of Th1/Th2 cells,In 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 secret

11、e in response to antigenic stimulation.,,,,,,Induction of Th1 and Th2 Responses,,Th2,Th1,,,,,,,,Antigens,IL-4,IL-12IFN-γ,APC,Naïve CD4,Effector Cells,Signal 2,Signal 1,IL-2IFN-γ,IL-4IL-5IL-10,Cellular Immune Res

12、ponses,Humoral Immune Responses,,,Leishmania major Infection in Mice Provides a Useful Model to Study Th1 and Th2 Differentiation and Memory in vivo,Leishmania major infection: Mouse Models,Balb/C,BL/6,,,,,,Th 1 respon

13、se,,Death,Recovery,Th 2 response,,,IL-12,αIL-12/αIFN-γ,Signaling of IL-12 Receptor,,,Expression?1: Expressed on Th1, Th2, N.K., and B cells?2: Expressed on activated Naïve T, Th1, and N.K. cells,RegulationEnhance

14、d by: activation of ?-CD28, IL-2, IL-7, IL-15, IFN-? (mouse), IFN-? (human)Inhibited by: IL-4, IL-10, TGF-?, PGE2, Dex,,Cytokines On Th1 Cell Development,,,,,,Pathogen,APC,CD4+T Cell,STAT4,TCR,IFN-γ,IFN-γ+++,IL-27,TCCR

15、/WSX-1,,,,IL-12,IL-12,IL-23,IL-12,IL-18,IL-18,,,,Naïve CD4+,Th1,Th1 Effector,IL-12Rβ1,β2,IL-18R,IL-18R,IL-12Rβ1,IL-12Rβ1,IL-12Rβ1,β2,β2,,STAT1,,T-bet,,IFN-γ,,T-bet,,,STAT4,,,STAT4,,,,NFKBGADD45p3B,IRAKNFKB,,,如果敲

16、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,(2)分泌細(xì)胞因子參與免疫調(diào)節(jié),22,,Interleukin-9 (IL-9)-producing T cells (Th9 Cells) 肥大細(xì)胞、過敏反應(yīng),Introduction,Recently, two reports described a discrete subset of inte

17、rleukin-9(IL-9)-producing T cells that might be closely related to the TH2-cell lineage.These IL-9-producing T cells seem to be a distinct population that does not show the characteristics of other described T-cell sub

18、sets------“TH9” cells.,25,26,TGF-β deviates TH2 cells to a “TH-9” fate,IL-9-producing T cells could be generated from TH2 cells that were exposed to TGF-β in vitro, even when the TH2 cells were highly polarized.,×

19、,IL-4 inhibits TGF-β-induced Foxp3+ T cellsIL-4 actively inhibits the induction of Foxp3 in the presence of TGF-β.The inhibition of Foxp3 expression by IL-4 is mediated through the IL-4-STAT6 pathway.The Foxp3 can d

20、irectly interact with GATA-3 and this association inhibits GATA-3 mediated transactivation of IL-5, which is one of its target genes.,,,,,,,,,,,CD4+,CD8+,CD4+25+,28,效應(yīng)----調(diào)控 過強(qiáng)和過弱,The Role of Suppressor or Regulatory T

21、Cells (Treg) in Immunity,Introduction,Regulation of immune responses to self-antigen is a complex processMaintaining self-toleranceRetaining the capacity to mount immune responses against invading microorganisms,Discov

22、ery of Suppressor T Cells,In 2019, 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-speci

23、fic autoimmune diseases in the majority of recipients.The minor subpopulation of cells are CD4+CD25+ T cells.,Discovery of Suppressor T cells,CD4+CD25+ Regulatory T cells,A unique lineage of regulatory T cells capable o

24、f maintaining self tolerance in vivo,33,,T,CD8,CD4,CD4+25+,,,,Th1,Tc2,Tc1,Th2,Th3,Tr1,,,,,,,,,Peripheral T lymphocyte,,,5-10%,30%,Th4?,,,,60%,Thymus,34,Overview of phenotypes and functions of CD4+ T cells,NaïveCD4

25、,Th1,Tr,Th2,,,,IFN-γ,Cell mediated immune responses,IL-4 IL-5 IL-10 IL-13,humoral immune response,,,,,,,,Tr 1,Th 3,CD4+CD25+,,,,High IL-10 , low TGF-β,TGF-β,cell-cell contact,,Natural Tr in thymus

26、 contact-dependentAdaptive Tr in peripheral lymphoid tissue cytokines-dependant,Regulatory T cells,CD4+CD25+ Tr cells: Comprise 5-10% of peripheral CD4 T cells in human and miceProduced in th

27、ymus as an unique lineage of CD4 T cellsSecret IL-10 and/or TGF-b, but little IL-2Anergic and suppressive,CD45RBlow, CTLA-4 high,36,淋巴細(xì)胞及其亞群分析,①T淋巴細(xì)胞及亞群： 外周血中成熟淋巴細(xì)胞主要屬于TCRαβ＋T細(xì)胞，可分為Th、Ts、Treg，TCRγδT細(xì)胞和NK1.1

28、＋T細(xì)胞等，他們都有一個(gè)共同的標(biāo)志CD3。,37,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)CD3＋CD4＋CD8－。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)CD3＋CD4 －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CD4＋CD25＋FoxP3＋。

29、,38,d、Th /Ts比例，一般采用CD4 /CD8比例，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CD8＋T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；,39,②B細(xì)胞及亞群；B

30、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。③NK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)中具有重要作用。④DC: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+。,40,臨床意義,①總T和總B及其亞群的意義總T（50-84%）和總B（5-18%）可以