细胞亚群进展及临床意义.ppt

T细胞亚群进展及临床意义,1,医学免疫学,上海第二医科大学免疫教研室,2,医学免疫学,上海第二医科大学免疫教研室,3,T 细胞亚群与功能,根据TCR种类 TCR-1（TCR），TCR-2（TCR ）,根据TCR-2（TCR ）表达CD4或CD8的不同 CD4+T分子表型为CD2、CD3、CD4 CD8+T分子表型为CD2、CD3、CD8,根据功能 Th、Tc、Ts、TDTH,根据对抗原的应答不同 初始T细胞、抗原活化过的T细胞、记忆性T细胞,T细胞亚群,CD4 + 、CD8 +亚群 CD4+T细胞识别由1317个氨基酸残基组成的抗原肽，并受自身的MHC II类限制。CD8 + T细胞识别810个氨基酸组成的抗原肽，并受MHC I类限制。 TCRT细胞和TCRT细胞,6,Th、Tc、Ts和TDTH细胞 Th细胞 根据所分泌的细胞因子不同，将其分为Th0、Th1和Th2亚型。 Tc细胞 Tc1细胞主要分泌IFN；Tc2细胞则主要分泌IL-4、IL-5和IL-10。 Ts细胞 TDTH 主要为CD4 + Th1,7,（一）TCR T细胞 和 TCR T细胞,TCR 极大多态性 极少多态性 分布 外周血 60-70% 5-15% 组织 外周淋巴组织 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% 识别抗原 8-17aa 简单多肽、HSP、脂类、多糖 MHC限制 经典MHC分子 MHC类似分子 辅助细胞 Th细胞 杀伤细胞 Tc细胞 Tc细胞,特性 TCR T细胞,TCRT细胞,按CD分子不同,按功能不同,T细胞,CD4T细胞,CD8T细胞,辅助性T细胞(Th),细胞毒性T细胞(CTL或Tc),抑制性T细胞(Ts),CD4T细胞 CD表型：CD3+CD4+CD8-，主要为Th细胞亚群,识别抗原时受MHC-类分子限制 通过分泌细胞因子发挥效应功能 CD4T细胞(部分)也具有细胞杀伤功能,作用特点,1.CD4+Th细胞及其功能,2. CD8T细胞 CD表型：CD3+CD8+CD4-，主要为CTL细胞亚群,识别抗原时受MHC- 类分子限制 免疫调节作用, 如释放IFN-、TNF-和TNF-等细胞因子 具有细胞杀伤功能,作用特点,CD8+杀伤性T细胞 CTL的主要作用是直接杀伤靶细胞，有两种机制：细胞裂解和细胞凋亡,12,13,CD8+Tc细胞（CTL）及其功能,免疫应答的主要效应细胞，在肿瘤免疫和抗病毒免疫中发挥重要作用（抗肿瘤）,作用特点：特异直接杀伤靶细胞，在杀伤过程中自身不受损伤，可反复连续杀伤。,作用机制：细胞裂解（cytolysis） 细胞凋亡 （apoptosis）,抗肿瘤,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基因细胞免疫功能下降80%,T淋巴细胞的功能,(1)介导细胞免疫应答,(2)分泌细胞因子参与免疫调节,22,Interleukin-9 (IL-9)-producing T cells (Th9 Cells) 肥大细胞、过敏反应,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,效应-调控 过强和过弱,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,淋巴细胞及其亚群分析,T淋巴细胞及亚群： 外周血中成熟淋巴细胞主要属于TCRT细胞，可分为Th、Ts、Treg，TCRT细胞和NK1.1T细胞等，他们都有一个共同的标志CD3。,37,a、辅助/诱导性T淋巴细胞（Th）占27-51%，是主要的功能亚群，主要表达CD3CD4CD8。 b、抑制/细胞毒性T淋巴细胞（Ts）占15-44%，是主要的效应性T细胞亚群，主要表达CD3CD4 CD8。 c、Treg细胞是近年来新发现的一个T淋巴细胞亚群，具有重要的免疫调节功能，在自身免疫病、肿瘤和器官移植排斥反应中具有重要作用，主要标志为CD4CD25FoxP3。,38,d、Th /Ts比例，一般采用CD4 /CD8比例，正常值2：1，免疫力低下时比例倒置。 e、T淋巴细胞的绝对计数，在某些疾病中T淋巴细胞会大量减少；CD4和CD8T细胞均减少。 f、T淋巴细胞活化；CD69正常情况下极少表达，早期出现CD69表达，中期CD69、CD25（IL-2R）表达，晚期出现CD71（转铁蛋白受体）和HLA-DR表达。 g、初始T细胞和记忆T细胞亚群表达见157；,39,B细胞及亚群；B细胞在外周血占5%-15%，与自身免疫疾病、B细胞系的肿瘤关系密切；B慢性淋巴细胞白血病与淋巴瘤等主要表达CD19、20、21、22。 NK细胞：外周血占10%，CD16、CD56是特异性标志。NK细胞在抗感染、抗肿瘤和移植排斥反应中具有重要作用。 DC:是