一种新的共刺激信号CD137在人T细胞及其亚群中的表达特点①

目的为了分析CD     

共刺激信号对调节性T细胞的调控

机体免疫系统中的自身调节对限制免疫应答反应造成的破坏作用和自身稳定是十分重要的。许多自身免疫性疾病发病和免疫机制的调节平衡通路现已较为清楚。调节通路中缺少了某些分子如CTLA 4、TGF β、FoxP3等, 可以造成致死性损害。近年来关于CD4 CD25 特异性T抑制性细胞 (又称调节性T细胞或Tregs)的研究已经取得了令人瞩目的进展,可以肯定地说, CD4 CD25 Tregs作为一个具有独立功能的T细胞亚群, 在维持免疫系统平衡过程中有着不可替代的作用。有关这些细胞的作用机理和免疫生物学特性尚有许多不明之处, 该类细胞的特异性膜表…     

一种新的T细胞共刺激分子—4—1BB

4-1BB是一种新发现的T细胞共刺激分子，属于TNFR/NGFR超家族成员，近年来发现它在T淋巴细胞的活化，增殖，分化及凋亡等诸多方面发挥了重要的生物学功能。4-1BB介导的活化信号主要是通过TPKp56^lck和TRAF的途径转导入胞内，本文拟就4-1BB的有关问题作一综述。     

Graves病患者外周血T细胞亚群和共刺激分子的表达及其意义

为研究Graves病患者外周血T细胞亚群及共刺激分子的表达 ,并探讨其在Graves免疫病理机制中的作用 ,本文采用免疫荧光标记和流式细胞仪术检测了 19例Graves病患者和 11例正常人外周血T细胞亚群及共刺激分子 (CD2 8、B7、CD40、CD40L、 4 1BB、OX40 )的表达。结果表明 ,19例初诊Graves病患者外周血T细胞亚群呈现异常改变 ,表现为CD3+ 和CD4+T细胞显著下降 (P <0 0 5 ,P <0 0 1) ,CD4+ /CD8+ T细胞比值倒置 (P <0 0 1) ,共刺激分子CD2 8在T细胞中的表达水平明显下降 (P <0 0 1) ,T细胞亚群CD4+ CD2 8+ 、CD8+ CD2 8+ 细胞数量均减少 (P <0 0 5 ,P <0 0 1) ,而 4 1BB分子表达显著地升高 (P <0 0 5 )。随防 10例治疗后缓解患者 ,T细胞亚群失衡明显改善 ,共刺激分子CD2 8的表达水平上调 (P <0 0 1) ,而4 1BB分子的表达明显下降 (P <0 0 1) ,T细胞亚群CD4+ CD2 8+ 、CD8+ CD2 8+ 细胞数量均增加 (P <0 0 1) ,甲状腺自身抗体甲状腺球蛋白抗体 (TGAb )和甲状腺微粒体抗体 (TMAb )的表达水平均下降 (P <0 0 1,P <0 0 1)。从而表明 ,T细胞亚群的异常及共刺激分子CD2 8、 4 1BB的表达改变与Graves病的免疫病理机制相关。     

LIGHT 一个新的非CD28依赖的T细胞共刺激分子

ＬＩＧＨＴ(ｆｏｒｈｏｍｏｌｏｇｏｕｓｔｏｌｙｍｐｈｏｔｏｘｉｎｓ ,ｅｘｈｉｂｉｔｓｉｎ ｄｕｃｉｂｌｅｅｘｐｒｅｓｓｉｏｎ ,ａｎｄｃｏｍｐｅｔｅｓｗｉｔｈＨＳＶｇｌｙｃｏｐｒｏｔｅｉｎＤｆｏｒＨＶＥＭ ,ａｒｅｃｅｐｔｏｒｅｘｐｒｅｓｓｅｄｂｙＴｌｙｍｐｈｏｃｙｔｅｓ) 〔1〕是1998年发现的ＴＮＦ超家族成员 ,又称为ＨＶＥＭ Ｌ(ｈｅｒｐｅｓｖｉｒｕｓｅｎｔｒｙｍｅｄｉａｔｏｒ ｌｉｇａｎｄ) 〔2〕 是肿瘤坏死因子超家族的第 14个成员 (ＴＮＦＳＦ14)。由于ＬＩＧＨＴ同时具有诱导肿瘤细胞凋亡和共刺激Ｔ细胞活化的…     

rIL-2、IFN-γ和胸腺肽对T细胞共刺激信号分子CD137表达的影响

外周血静止T细胞成为有功能活性T细胞需两个独立的刺激信号系统 ,即第一信号 (MHC 抗原肽 TCR CD3)和第二信号刺激系统。而CD137和CD137配体是新近发现的除CD2 8 B7之外的另一对关键的第二刺激信号 ,并引起人们的注意〔1,2〕。本研究用流式细胞仪检测健康人外周血单个核细胞经rIL 2、IFN γ和胸腺肽刺激后T细胞及其亚群共刺激信号分子CD137表达的特点 ,以比较、了解三者对共刺激信号分子CD137表达的影响。材料和方法主要试剂 :基因重组人IL 2 (rIL 2 ) ,军事医学科学院基础医学研究所、北京瑞得四环生物技术研究所联合研制产…     

一种新的T细胞共刺激分子——4-1BB

4 1BB是一种新发现的T细胞共刺激分子 ,属于TNFR NGFR超家族成员 ,近年来发现它在T淋巴细胞的活化、增殖、分化及凋亡等诸多方面发挥了重要的生物学功能。 4 1BB介导的活化信号主要是通过TPKp5 6 lck和TRAF的途径转导入胞内。本文拟就 4 1BB的有关问题作一综述。     

共刺激分子CD40L在RA患者T细胞亚群中的异常表达

目的　探讨共刺激分子CD4 0L在类风湿关节炎 (RA)患者的T细胞亚群上的表达异常与免疫功能紊乱的关系。方法　用流式细胞仪采用直接免疫荧光法测定 4 6例RA患者和 2 0例健康对照人外周血T细胞表面标志CD3、CD4、CD8的表达情况及CD4 0L在CD4 + T和CD8+ T细胞上的表达。用IMMAGE免疫分析仪 ,速率散射比浊法测定血清中免疫球蛋白的水平。结果　RA患者CD3+ CD4 + 细胞较正常对照组显著增高 (P <0 .0 5 ) ,CD3+ CD8+ 细胞较正常对照组显著降低 (P <0 .0 5 ) ,CD4 + T细胞和CD8+ T细胞上的CD4 0L的表达都较对照组显著增高 (P <0 .0 5 ) ;血清中 3种免疫球蛋白IgG、IgA、IgM的水平均较对照组显著增高 (P <0 .0 5 )。结论　RA患者以CD4 + T细胞活化为主 ,CD4 + T细胞和CD8+ T细胞上高表达的CD4 0L为T细胞活化提供第二信号 ,促使RA患者的细胞免疫功能亢进 ,同时诱导B细胞增生 ,产生大量免疫球蛋白。CD4 0 CD4 0L途径在RA免疫功能紊乱中起了重要作用     

CD137在SLE和RA病人外周血T细胞上的表达特点及意义

ＣＤ137是一种新的Ｔ细胞共刺激分子。最近研究显示 ,ＣＤ137和ＣＤ137配体 (ＣＤ137Ｌ)可能为ＣＤ2 8/Ｂ7之外的另一对关键的共刺激信号分子 ,开始引起人们的注意。目前国外有关ＣＤ137的研究主要来自鼠 ,在人方面的研究尚少 (至 1999年 9月仅有 14篇报道 ) ,许多问题尚不清楚。国外虽已研究了ＣＤ137在正常人Ｔ细胞表达 ,但有关ＣＤ137在自身免疫病病人的表达特点尚无报道。我们在研究了ＣＤ137在正常人外周血Ｔ细胞表达的基础上 ,进一步分析了ＣＤ137在系统性红斑狼疮 (ＳＬＥ)和类风湿性关节炎(ＲＡ)病人Ｔ细胞的表达特点。材料和方法材…     

026 一种新的T细胞共刺激分子——4-1BB

4-1BB是一种新发现的T细胞共刺激分子,属于TNFR/NGFR超家族成员,近年来发现它在T淋巴细胞的活化、增殖、分化及凋亡等诸多方面发挥了重要的生物学功能.4-1BB介导的活化信号主要是通过TPKp56lck和TRAF的途径转导入胞内.本文拟就4-1BB的有关问题作一综述.     

CD137(人4-1BB)在dhfr-CHO中的表达及活性研究

目的 :构建CD137真核高效表达系统 ,深入研究CD137及其配体在细胞信号转导中的作用。方法 :将构建有CD137全长cDNA序列的pCDNA3质粒 (CMV ILA SEN ,CIS)及pSV2 dhfr(含二氢叶酸还原酶基因 ) ,运用脂质体介导法共转染二氢叶酸还原酶缺陷的CHO细胞 (dhfr CHO) ;用G4 18筛选出阳性克隆 ;MTX压力选择系统诱导CD137在dhfr CHO细胞的高效表达 ;RT PCR、免疫细胞化学法及流式细胞术测定CD137的表达情况 ;3H TdR掺入法进行活性研究。结果 :CD137为膜型表达 ,CIS转化dhfr CHO细胞CD137表达率为 96 0 7% ;活性研究显示CD137膜蛋白轻度促进抗CD3单抗诱导的PBMC增殖。结论 :获得高效表达CD137的CHO细胞株 ,CD137膜蛋白促进抗CD3单抗诱导的PBMC增殖。     

Combined CD137 (4-1BB) and adjuvant therapy generates a developing pool of peptide-specific CD8 memory T cells

In practice, vaccines should induce lasting and efficaciousT cell immunity without promoting deleterious pathological consequences.To accomplish this goal we immunized mice with ovalbumin peptide,polyinosinic–polycytidylic and anti-CD137. Vaccinatedmice retained a massive functional CD8 T cell memory pool inlymphoid and non-lymphoid tissues for >1 year. The memoryT cells clonally expanded, produced substantial amounts of IFN,and responded vigorously to vesicular stomatitis virus infection.To understand how the vaccine might function, we showed thatthe antigen-specific T cells must bear CD137 in order for optimalpriming to occur. Thus, anti-CD137 agonist mAb directly stimulatedpeptide-specific CD8 T cells and conditioned them to survive.In contrast, CD137-deficient CD8 T cells did not survive despiteCD137 expression by antigen presenting cells. Taken together,the data indicate that CD137 and adjuvant combined therapy isan efficacious vaccine strategy for immunization with non-replicatinginert antigen.     

亚急性衰老小鼠脾脏T细胞CD137表达的研究

目的：探讨CD137分子在衰老小鼠脾脏T细胞表面表达的规律。方法：通过注射D－半乳糖建立亚急性衰老小鼠模型。分离衰老模型组小鼠及正常对照组小鼠的脾脏T细胞，经Con A刺激后进行培养，采用流式细胞术检查Con A刺激后不同培养时间的T细胞上CD137的表达，并进行比较。结果：小鼠脾脏T细胞经过Con A刺激后，正常对照组小鼠T细胞上CD137分子的表达高峰出现于刺激后第6天，平均表达率为48．5％，之后迅速下降。1个月和2个月衰老模型组小鼠T细胞上CD137分子在表达高峰的表达率平均分别为39．1％和32．8％，均显著低于正常对照组小鼠（P＜0．01），其中1个月模型组小鼠T细胞上CD137分子表达高峰的出现时间及下降规律与正常对照组小鼠相同；而2个月衰老模型组小鼠T细胞上CD137分子的表达高峰出现于刺激后第4天，第9天缓慢下降至与正常对照组相同时间的水平。结论：亚急性衰老小鼠T细胞上CD137分子的表达低于正常水平。至衰老过程的后期，T细胞上CD137分子的表达高峰提前出现，表达水平达到峰值后下降速度较正常小鼠缓慢，提示CD137分子在机体抗衰老过程中，具有调节T细胞功能的作用。     

TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation

1. Download : Download high-res image (163KB)
2. Download : Download full-size image

     

A distinct role for ICOS-mediated co-stimulatory signaling in CD4+ and CD8+ T cell subsets

While the ligand of inducible co-stimulator (ICOS), B7 homologous protein, is widely expressed in somatic cells, B7-1 and B7-2 expression is mainly limited to lymphoid organs. Thus, the activation of T cells through ICOS without a CD28-mediated signal may occur in physiological situations. In order to gain a better understanding of the role of the ICOS co-stimulatory signal in immune responses, we studied the cellular response of T cells to beads coated with anti-ICOS or anti-CD28, plus sub-optimal anti-CD3 mAb. We demonstrate that while CD28 ligation induced expansion of both CD4+ and CD8+ populations, ICOS ligation only resulted in the expansion of CD8+ T cells, and induced apoptosis in the CD4+ T cell population. It was found that IL-2 is critically required for CD8+ T cell expansion triggered by ICOS ligation, whereas it had only a limited effect on the expansion of CD4+ T cells. This distinct reactivity of CD4+ and CD8+ T cell populations to exogenous IL-2 strongly correlates with the expression level of IL-2 receptor beta-chain, CD122, on T cells. Furthermore, we defined a small but distinct population of memory phenotype CD4+ T cells that constitutively express ICOS. Interestingly, while naive CD4+ T cells were unable to produce IL-2, ICOS-expressing T cells produced a substantial amount of IL-2 by stimulation with anti-ICOS/CD3 beads, suggesting that IL-2, which is indispensable for CD8+ T cell expansion, is produced by this ICOS-expressing T cell population. These results provide evidence indicating that the ICOS co-stimulatory signal plays a distinct role in the development of CD4+ and CD8+ T cell-mediated immune responses.     

喘可治延长小鼠异基因移植皮片存活时间与CD4+CD25+调节性T细胞相关性研究

目的：研究喘可治抑制小鼠异基因皮片移植排斥作用与小鼠体内CD4+CD25+ 调节性T细胞（CD4+CD25+Tr）变化的相关性。 方法： 建立小鼠同种异基因与同基因皮片移植模型，通过腹腔注射给药喘可治(CKZ)观察其对皮片移植存活时间的影响，并利用3色免疫荧光标记和流式细胞术分析受鼠外周血CD4+CD25+ Tr变化规律。 结果： 同种异基因移植CKZ组的移植皮片存活时间显著长于同种异基因移植对照组，分别为（195±23）d和（102±22）d，P＜001；在同种异基因皮片移植后，受体外周血CD4+CD25+ Tr占CD4+T细胞百分率明显升高，术后8 d达到高峰（P＜001），然后出现下降趋势，其中同种异基因移植对照组在术后13 d时已回落至正常水平，而同种异基因移植CKZ组在术后23 d时仍维持在高于移植前水平；在同基因皮片移植后，CKZ组与对照组外周血CD4+CD25+ Tr水平均无明显升高（P＞005）。 结论： 喘可治可延长小鼠同种异基因移植皮片存活时间，通过升高CD4+CD25+ Tr水平而发挥免疫抑制效应可能是其机制之一。     

Involvement of 4-1BB (CD137)-4-1BBligand interaction in the modulation of CD4 T cell-mediated inflammatory colitis

4-1BB ligand (4-1BBL) expressed on antigen-presenting cells interacts with 4-1BB on activated T cells (especially CD8+ cells) and co-stimulates the latter to secrete cytokines and to proliferate. The role of 4-1BB-4-1BBL interaction was studied here in a model of colitis based on naive CD4+ T cell transfer to SCID mice, a disease model in which CD8 cells do not take part. We found that CD4+ T cells from 4-1BB-deficient mice, after transfer in SCID mice, proliferated more rapidly compared to wild-type CD4+ T cells. Mice reconstituted with naive CD4+ T cells from 4-1BB-deficient mice developed colitis, however, with a mixed Th1/Th2 response, in contrast to the Th1-type response in mice reconstituted with wild-type naive CD4+ T cells. Importantly, this altered cytokine response did not temper colitis severity. Although it has been reported previously that 4-1BB co-stimulation may contribute to regulatory T cell functioning, we found that CD4+CD25+ regulatory T cells from 4-1BB-deficient mice were perfectly able to prevent naive CD4+ T cell-induced colitis. In conclusion, our data provide evidence that 4-1BB-4-1BBL interaction modulates the effector CD4+ T cell-driven immune response and cytokine production in experimental colitis without affecting regulatory T cell function.     

Clonal analysis of CD4 mediated accessory function on the effector activity of human CD4+ T cell subsets

Background: It has been reported for the peripheral T cell repertoire that CD4 molecules may enhance adhesion between T cells and antigen presenting cells and, through their physical association with T cell antigen receptors, contribute to signal transduction. Objective: The aims of this study were to determine if the modulation of CD4 molecules had differential effects on T cell recognition, antigen induced cytokine (IL-4 and IFNγ), release and the induction of specific anergy for human TH-0, TH-1 and TH-2 cells. Methods: A panel of anti-CD4 antibodies was examined for its ability to modulate T cell proliferation, cytokine production and tolerance induction in house dust mite (TH-0 and TH-2) and influenza haemagglutinin (TH-1) specific human CD4+ T cell clones all restricted by DRB1^*1101 and isolated from dust mite allergic individuals. Results: We observed that anti-CD4 antibodies may inhibit or enhance antigen mediated T cell proliferation, which may reflect the differential requirements of T cells for selective functions of CD4. Furthermore, IFNγ and IL-4 production was differentially modulated depending on the specificity of the anti-CD4 antibody and the clone of T cells. However, pretreatment of T cells with anti-CD4 antibody alone neither induced nor enhanced the susceptibility of T cells to peptide mediated anergy. Conclusion: Antigen recognition by different subsets of human CD4+ T cells has differential requirements on CD4, whereas the induction of specific anergy appeared to be independent of the functions of CD4 molecules. Antigen induced IFNγ production was more susceptible than IL-4 to the inhibitory effects of anti-CD4 antibodies. Furthermore, it appeared that certain anti-CD4 antibodies can dissociate antigen induced IFNγ and IL-4 production, and may downregulate IFNγ synthesis without inhibiting antigen dependent proliferation.