最新T细胞亚群进展及临床意义PPT文档.ppt
,医学免疫学,上海第二医科大学免疫教研室,1,医学免疫学,上海第二医科大学免疫教研室,2,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,5,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+Th1,6,（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,11,12,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-12IFN-,APC,Nave CD4,Effector Cells,Signal 2,Signal 1,IL-2IFN-,IL-4IL-5IL-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,Expression1:Expressed on Th1,Th2,N.K.,and B cells2:Expressed on activated Nave T,Th1,and N.K.cells,RegulationEnhanced 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,NFKBGADD45p3B,IRAKNFKB,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,21,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.,24,25,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 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 mediated transactivation of IL-5,which is one of its target genes.,CD4+,CD8+,CD4+25+,27,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 processMaintaining self-toleranceRetaining 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,32,T,CD8,CD4,CD4+25+,Th1,Tc2,Tc1,Th2,Th3,Tr1,Peripheral T lymphocyte,5-10%,30%,Th4?,60%,Thymus,33,Overview of phenotypes and functions of CD4+T cells,NaveCD4,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-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 thymus as an unique lineage of CD4 T cellsSecret IL-10 and/or TGF-b,but little IL-2Anergic and suppressive,CD45RBlow,CTLA-4 high,35,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。,36,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。,37,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；,38,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:是重要的抗原提呈细胞分为髓样CD1淋巴样CD2。重要标志CD11c+、HLA-DR+。,39,临床意义,总T和总B及其亚群的意义总T（50-84%）和总B（5-18%）可以用来判断某些免疫缺陷和自身免疫性疾病。对CD4和CD8T细胞的测定有助于免疫缺陷疾病、自身免疫性疾病、移植排斥反应的监测。CD4/CD8的意义评价自身免疫失调、免疫失调或免疫缺陷病病人的免疫状态，监测骨髓移植病人以免受到急性GVHD的攻击。（自免病比值升高，病毒感染、肿瘤、再障比值降低）。NK细胞的意义NK（7-40%）细胞能够介导对某些肿瘤细胞和病毒感染细胞的细胞毒性作用。,40,
