細(xì)胞亞群進(jìn)展及臨床意義.ppt

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、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1317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,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、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 + 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% 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% CD4-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 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,TCRT細(xì)胞,按CD分子不同,按功能不同,T細(xì)胞,CD4T細(xì)胞,CD8T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),CD4T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-類分子限制 通過分泌細(xì)胞因子發(fā)揮效應(yīng)功能 CD4T細(xì)胞(部分)也具有細(xì)胞殺傷功能,作用特點(diǎn),1.CD4+Th細(xì)胞及其功能,2. CD8T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- 類分子限制 免疫調(diào)節(jié)作用, 如釋放IFN-、TNF-和TNF-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）,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 secrete in response to antigenic stimulation.,Induction of Th1 and Th2 Responses,Th2,Th1,Antigens,IL-4,IL-12 IFN-,APC,Nave CD4,Effector Cells,Signal 2,Signal 1,IL-2 IFN-,IL-4 IL-5 IL-10,Cellular Immune Responses,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 response,Death,Recovery,Th 2 response,IL-12,IL-12/IFN-,Signaling of IL-12 Receptor,Expression 1: Expressed on Th1, Th2, N.K., and B cells 2: Expressed on activated Nave T, Th1, and N.K. cells,Regulation Enhanced 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-,IFN-+,IL-27,TCCR/ WSX-1,IL-12,IL-12,IL-23,IL-12,IL-18,IL-18,Nave CD4+,Th1,Th1 Effector,IL-12R1,2,IL-18R,IL-18R,IL-12R1,IL-12R1,IL-12R1,2,2,STAT1,T-bet,IFN-,T-bet,STAT4,STAT4,NFKB GADD45 p3B,IRAK NFKB,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,(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 interleukin-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 subsets-“TH9” cells.,25,26,TGF- deviates TH2 cells to a “TH-9” fate,IL-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 cells IL-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 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 Cells (Treg) in Immunity,Introduction,Regulation of immune responses to self-antigen is a complex process Maintaining self-tolerance Retaining the capacity to mount immune responses against invading microorganisms,Discovery 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-specific 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 of 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,Nave CD4,Th1,Tr,Th2,IFN-,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-,TGF-,cell-cell contact,Natural Tr in thymus contact-dependent Adaptive 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 mice Produced in thymus as an unique lineage of CD4 T cells Secret IL-10 and/or TGF-b, but little IL-2 Anergic and suppressive,CD45RBlow, CTLA-4 high,36,淋巴細(xì)胞及其亞群分析,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。,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)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。,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；,39,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)中具有重要作用。 DC:是