CD27-CD70在淋巴细胞中的作用

CD27及其配体CD70属于肿瘤坏死因子-肿瘤坏死因子受体超家族,是一对共刺激分子,在T、B、NK细胞的活化、增殖中起重要作用,而且CD27通过CD70可精确地调节免疫应答的程度和持续的时间.CD27被认为是CD4+CD25+细胞(Tr)的一个标记,可以鉴别调节性和非调节T细胞;CD27在B细胞上的表达可促进生发中心的形成并存在于记忆性B细胞上.CD27分子参与调节NK细胞的增殖与活化,可能与NK细胞的自然免疫监视及NK细胞主动攻击表面表达CD70的病毒感染细胞及突变细胞密切相关.而体内体外试验均表明CD70是B细胞上的一个抑制信号,CD70可抑制浆细胞的形成,且树突状细胞上CD70的功能不能被其它共刺激分子所替代.CD27-CD70有可能成为自身免疫性疾病又一个新的治疗靶点.     

CD40-CD40L共刺激分子与自身免疫性疾病

大量研究证实CD4 0分子与其配体CD4 0L结合所产生的共刺激信号在B细胞的增殖、分化、抗体的分泌和类型转换以及T细胞活化、效应性细胞因子分泌中起重要作用。近年来发现 ,CD4 0、CD4 0L异常表达与一些疾病的免疫病理密切相关。本文仅就CD4 0 CD4 0L的生物学特性、功能和在自身免疫性疾病中的致病作用及其可能的治疗策略作一综述     

129 CD40-CD40L共刺激分子与自身免疫性疾病

大量研究证实CD40分子与其配体CD40L结合所产生的共刺激信号在B细胞的增殖、分化、抗体的分泌和类型转换以及T细胞活化、效应性细胞因子分泌中起重要作用.近年来发现,CD40、CD40L异常表达与一些疾病的免疫病理密切相关.本文仅就CD40-CD40L的生物学特性、功能和在自身免疫性疾病中的致病作用及其可能的治疗策略作一综述.     

自身免疫性疾病的诊断

免疫酶技术的发展使自身免疫性疾病的诊断水平有了很大提高。Ｗｅｓｔｅｒｎ印迹分析技术的应用使一些自身抗原能够定性：ＥＬＩＳＡ技术为诊断系统性红斑狼疮，硬皮病，类风湿性关节炎等自身免疫性疾病提供了更为快捷和安全的方法。     

自身基因与自身免疫性疾病

自身免疫性疾病与自身免疫不同，后者是由于年龄等因素造成的正常情况，一般来讲是可逆的或是生理性的。而前者是由于基因、病毒、激素和神经内分泌免疫调节因素的改变造成的对机体正常功能的损伤。自身基因（autogene）的概念把自身免疫性疾病的成因，归结到了免疫反应调节基因的水平，从最根本上，提出了了解和控制自身免疫性疾病的新途径。本文拟从目前已经明确的自身基因（如Fas和bcl-2）入手，通过分析这些基因与细胞凋亡的关系，说明自身免疫性疾病发病的分子机制。     

自身免疫性疾病的基因治疗

随着对自身免疫病认识不断深入 ,新的治疗策略受到关注。通过对抗原特异性自身反应性T细胞和自身免疫靶细胞基因修饰 ,靶向性治疗自身免疫病的研究引人瞩目。目前基因治疗已应用于自身免疫病动物模型 ,并初步取得令人满意的结果。本文就此方面作一综述     

T细胞接种与自身免疫性疾病

用灭活自身反应性Ｔ细胞作为疫苗接种是近十多年来出现的一种新和自身免疫性疾病防治方法。该法已从动物实验走向了临床应用。由于Ｔ细胞接种具有特异的免疫抑制作用，因而在临床上展现了广阔和应用前景。     

神经内分泌激素与自身免疫性疾病

下丘脑垂体通过各自相应的轴所释放产生的神经内分泌激素，通过与免疫细胞表面相应的受体结合而影响机体免疫功能，近年来研究认为，多种自身免疫性疾病的发生，发展与神经内分泌激素失调存在一定的相关性。     

调节性B细胞与自身免疫性疾病

以往认为,B淋巴细胞在自身免疫病中作为致病性淋巴细胞发挥作用.近年却发现,在自身免疫病小鼠模型中,采用B细胞清除疗法会加重疾病进程,提示B细胞具有免疫调节功能.调节性B细胞(Breg)是新近发现的一群新的B细胞亚群,它存在于B细胞多个亚型中.Breg通过刺激其表面分子,诱导释放调节性细胞因子如IL-10发挥调节作用.在不同自身免疫性疾病中,各种免疫细胞都可以成为Breg作用的靶细胞,表明Breg在自身免疫病复杂网络中的强大调节作用.     

CD70 represents the human ligand for CD27

The recently identified CD27 ligand (L) Is a type II transmembranemolecule with significant structural homology to tumor necrosisfactor (TNF)-, TNF-ß, lymphotoxin ß, CO40L,and CD30L. Using a CD27L specific mAb we examined the tissuedistribution of the molecule, and found Its expression to berestricted to B cells in occasional germinal centers, stromalcells in the thymic medulla, and scattered T cells in tonsils,skin and gut. As the limited expression of CD27L closely resembledthe reported distribution of the activation antigen CD70, wetested whether CD70 represents the human CD27L. CD70 mAb werefound to react with CD27L-expressing transfected mouse fibroblasts.Moreover a number of CD70 mAb could specifically interfere withthe cellular binding of CD27L mAb. Thus, CD70 Is Identical tothe human CD27L.     

CD27/CD70 interaction directly drives B cell IgG and IgM synthesis

CD27 is a T cell activation antigen expressed on a majority of peripheral blood T cells. CD27 is also expressed on a subpopulation of human B cells, and it is reported that CD27⁺ B cells secrete both IgG and IgM. CD70, a ligand for CD27, is expressed on activated T and B cells, suggesting an interaction between T and B cells via CD27/CD70 ligation. Here, we analyze B cell immunoglobulin synthesis using a CD70 transfectant and present functional data showing that B cells secrete large amounts of IgG and IgM as a result of the CD27/CD70 interaction. A flow cytometric analysis showed that CD27 expression was increased and CD70 was expressed on tonsillar and peripheral blood B cells after activation with Staphylococcus aureus Cowan strain (SAC) plus interleukin (IL-2). In addition, the proliferation of B cells was enhanced mildly by the addition of CD70 transfectant, and its proliferation was blocked by anti-CD70 mAb. More importantly, the CD70 transfectant enhanced IgG and IgM production by purified B cells greatly in the presence of SAC plus IL-2. The enhancement was completely blocked by the addition of either anti-CD70 mAb or anti-CD27 mAb. Strongly suggesting that the interaction of CD27 with its ligand, CD70, on B cells plays an important role in B cell growth and differentiation to produce IgG and IgM.     

Phenotype and function of human B cells expressing CD70 (CD27 ligand)

CD70, the cellular ligand of the tumor necrosis factor receptor family member CD27, can be found on a limited number of germinal center (GC) B cells in some tonsils, on scattered lymphocytes residing in secondary lymphoid organs, and on a fraction of the circulating B cell population. Due to the restricted expression of CD70 in vivo, we analyzed signals that determine CD70 expression levels and characterized the phenotype and function of CD70⁺ B cells. Expression of CD70 on B cells activated in vitro was found to be dependent on the continuous presence of a B cell antigen receptor cross-linking agent, and induced or potentiated by CD40 ligation but was down-modulated by the Th2 cytokines interleukin (IL)-4 and IL-13. Both in peripheral blood and tonsil cell suspensions, CD70⁺ B cell subpopulations were found to be enriched for CD27-and IgG-expressing cells, but contained less IgD⁺ B cells. Additional analysis of markers which define specific differentiation stages (Bm1-5) of mature B cells within human tonsils did not place CD70-expressing B cells in one of these subsets. Functional experiments revealed that whereas both CD70⁻ and CD70⁺ B cells can secrete immunoglobulin after activation with a combination of Staphylococcus aureus Cowan strain I and IL-2, only CD70⁺ B cells can produce large quantities of antibodies when stimulated in a T cell-dependent fashion. Our combined data imply that CD70 is a marker for mature B cells which have recently been primed by antigen in vivo.     

Control of lymphocyte function through CD27–CD70 interactions

In contrast to the expression of other TNFR/TNF family members, expression of CD27 and its ligand CD70 is predominantly confined to lymphocytes. High expression levels of CD27 appear to be dependent on proper ligation of antigen receptors, whereas for the induction of CD70 expression additional (co–stimulatory and/or pro–inflammatory) signals are required. Next to membrane–bound CD27 also a soluble form of CD27 is produced in the course of the immune response. Soluble CD27 (sCD27) is found in body fluids and can be used to monitor local and systemic immune activation. In addition, elevated serum concentrations of sCD27 are found in patients with B cell malignancies and levels of sCD27 strongly correlate with tumor load. Based on functional experiments andin vitroexpression regulation data, we propose that interactions between activated lymphocytesin vivocan result in CD27–CD70 interactions that may regulate the size and function of antigen–primed lymphocyte populations.     

CD27 and CD70 do not play a critical role in the development of experimental allergic conjunctivitis in mice

CD27, which belongs to the TNF receptor family, is a costimulatory molecule that participates in T-cell activation. Unlike costimulatory molecules such as OX40 and 4-1BB, little is known about the role CD27 plays a role in the development of experimental diseases. We asked whether CD27 and its ligand CD70 participate in the development of experimental allergic conjunctivitis (EC) in BALB/c mice, which is generated by immunization with ragweed (RW) in alum and challenged 10 days later with RW in eye drops. The roles of CD27 and CD70 were tested by intraperitoneally injecting the mice with anti-CD27, anti-CD70 or a control Ab during the induction or effector phase. Twenty-four hours after challenge, the conjunctivas, blood and spleens were harvested for histological analysis, measuring Ig levels and cytokine analysis, respectively. Regardless of when the mice were treated, anti-CD27 or anti-CD70 Ab treatment did not significantly affect the severity of EC as evaluated by conjunctival eosinophil numbers. However, anti-CD27 or anti-CD70 Ab treatment during the induction phase did significantly modulate systemic humoral and cellular immune responses. In vitro treatment of RW-primed splenocytes with anti-CD27 or anti-CD70 Ab did not affect the EC-inducing capability of the splenocytes. Taken together, CD27 and CD70 do not play a critical role in the development of EC.     

Involvement of CD27/CD70 interactions in antigen-specific cytotoxic T-lymphocyte (CTL) activity by perforin-mediated cytotoxicity

CD27 molecules are shown to be essential in the regulation of the death, activation and differentiation of T and B cells. However, the influence of CD27 on cytotoxic T-cell function remains obscure. Autologous EBV transformed B-cell lines (LCL), which highly express CD27 ligand CD70, here stimulated T cells and induced the cytotoxic T-lymphocyte (CTL) activity via T-cell antigen receptors (TCR). The cytotoxicity against LCL was diminished when anti-CD70 blocking MoAb was added initially in the culture. Resting T cells killed more CD70-transfected P815 cells than wild type P815 cells in the presence of anti-CD3 MoAb as measured by a 4-h 51Cr release assay, and the cytotoxicity of both of the cell populations completely disappeared in the presence of concanamycin A (CMA). The expression of the perforin by the LCL-induced CTL in the presence of anti-CD70 blocking MoAb was diminished as compared with that without the blockage of CD27/CD70 interactions. The CTL induced by LCL did not kill Fas-transfected WR cells. CD27 signalling in the T cells did not affect Fas ligand (FasL) mRNA expression, LAK activity and IFN-gamma synthesis in humans. Our data demonstrate that CD27/CD70 interactions enhance the cytotoxicity of CTL in the induction phase through enhancement of killing activity induced via the perforin-dependent mechanism, but not via the Fas/FasL system.     

CD27/CD70 interactions regulate T dependent B cell differentiation

CD27 is a tumor necrosis factor (TNF) receptor family member whose expression is limited to cells of the lymphoid lineage. Constitutively expressed on T lymphocytes, it is a constimulatory molecule for a regulatory subset. Induced on B lymphocytes after antigenic challenge, it is a marker of memory cells. CD70, CD27 ligand, is a TNF related trans-membrane protein induced upon activation on T and B cells. In complement of ligation of CD40, another TNF receptor family member expressed by B cells CD27/CD70 interaction plays a key role in T dependent B cell responses and is responsible for plasma cell differentiation. B lymphocyte responses appear thus controlled by different T cell subsets expressing CD 154 (CD40 ligand), CD27, or CD70 (CD27 ligand).     

T cells compete by cleaving cell surface CD27 and blocking access to CD70‐bearing APCs

T cells compete against each other for access to molecules on APCs in addition to peptide/MHC complexes. However, the identity of cell surface molecules that influence T‐cell competition, other than peptide/MHC, have yet to be defined. Here, we identify CD70, a TNF ligand expressed on activated APCs, as an important mediator of T‐cell competition for APCs. Upon engagement of CD27 by CD70, CD27 is proteolytically cleaved from the surface of the interacting CD8⁺ T cell and captured by CD70 expressing dendritic cells. The capture of CD27 effectively masks CD70 on APCs, disallowing the interaction with CD27 on other competing T cells. Collectively, our data indicate that T cells compete against each other for access to the TNF‐ligand CD70, an interaction that affects the duration and potency of T cell/DC interactions, thus influencing the repertoire of responding CD8⁺ T cells to self or foreign antigens.