B7-2对肝细胞癌特异性免疫的影响

T细胞的激活需要两种信号刺激，第二信号为非抗原特异性，主要由协同刺激分子B7-2家族介导产生。我们将B7-2真核表达载体转染高度表达组织相容性复合物I(MHC-I)分子而缺乏MHC-Ⅱ分子的肝癌细胞株HMC7721，观察B7-2对CD8^ T细胞分化和肿瘤特异性免疫的影响。     

免疫检查点抑制剂在肝细胞癌治疗中的应用与展望

<正>免疫检查点(Immune checkpoint)抑制剂是近年来肿瘤免疫治疗领域取得的重大突破。免疫检查点是指T细胞表面存在的一些抑制性受体,当其与抗原递呈细胞上的配体结合后可抑制T细胞的功能。人体主要的免疫检查点有两个:细胞毒T淋巴细胞抗原4(CTLA-4)和程序性死亡因子1(PD-1)。CD28及其配体是抗原提呈细胞表面的B7分子,两者结合产生协同刺激信号,诱导T细胞活化。CTLA-4与CD28阳性T细胞有共同的配体B7-1和B7-2     

胃癌组织中B7-H3的表达及其与预后的关系

肿瘤免疫应答是由多种免疫细胞和分子参与并受到严格调控及制约的复杂生理过程,近年来越来越多的研究表明,一组细胞膜分子--共刺激分子（costimulatory mole-cules）,其调节性表达、相互作用及其信号传递在非常复杂的肿瘤免疫应答过程中起着极其重要的作用.B7家族作为惟一能从抗原递呈细胞（APC）单向传递信号至T细胞的共刺激分子[1],近几年已相继发现了B7RP-1（B7H、B7-H2）、B7-H1（PD-L1）、B7-DC（PD-L2）及B7-H3等新分子[2],从而使此家族的调节作用不断复杂化.B7-H3是新近克隆的B7家族成员,与其他B7家族分子有20%～27%的同源性[3],其研究才刚开始,在最新研究中发现,B7-H3能协同刺激CD4＋、CD8＋T细胞的增殖,使细胞毒T淋巴细胞（CTL）活性增加[4],被认为是一正性调控分子.B7-H3对胃癌细胞生物行为和胃癌预后的影响,目前国际上尚鲜有相关报道.     

调节性T淋巴细胞与桥本甲状腺炎

调节性T细胞抑制CD4+T细胞或CD8+T细胞的活化和增殖,在免疫应答中发挥重要的负调节作用,是维持自身免疫耐受的主要细胞之一.桥本甲状腺炎为遗传因素和多种内外环境因素影响的自身免疫性疾病.大量研究表明,调节性T细胞异常表达参与桥本甲状腺炎的发病.毒性T细胞相关抗原-4、CD28/B7协同刺激通路、粒细胞集落刺激因子、某些细胞因子等通过影响调节性T细胞的负调节作用而参与桥本甲状腺炎的发病.对调节性T细胞的深入研究有利于进一步阐明桥本甲状腺炎的发病机制并为桥本甲状腺炎的治疗提供新的方法.     

T细胞共刺激分子与自身免疫性疾病

T细胞的异常增殖和凋亡紊乱在自身免疫疾病的发生发展中起重要作用.T细胞的活化需要两个不同的信号.第一信号来自T细胞受体(TCR)与抗原肽-MHC复合物相互作用,第二信号来自抗原呈递细胞(APC)提供的共刺激信号.适宜的共刺激信号可以降低T细胞活化时对第一信号的需求,缺乏第二信号的活化可使T细胞无能;抑制性共刺激信号可以减弱免疫反应或导致免疫耐受.CD28、可诱导共刺激分子(inducible co-stimulator,ICOS)、OX40、CD137、CD40为主要的活化性共刺激分子,细胞毒T细胞相关抗原4(cytotoxic T-lymphocyteantigen4,CTLA4)、PD-1为抑制性共刺激分子.     

B7-1、GPI及其拼接在肿瘤免疫治疗中的应用进展

在肿瘤免疫过程中，T细胞是一类能够识别及杀伤肿瘤细胞的细胞，其作用发挥的前提是抗原递呈细胞（APC）将抗原呈递给T细胞。这一过程需要两个信号参与，一是由TCR／CD3复合物同MHCⅡ类分子相互作用．提供免疫应答中肿瘤相关的特异信号；另一个是共刺激信号，是由共刺激分子与其受体相结合，介导T细胞有效活化，并调节T细胞增殖反应。现已证明多数实体瘤不表达共刺激信号，导致T细胞无反应状态或免疫耐受。B7家族是重要的共刺激分子，B7-1与表达在T细胞上的CD28相结合，提供协同刺激信号，在引起T细胞的活化启动中起重要作用。糖基化磷脂酰肌醇（GPI）信号肽具有细胞膜锚定作用，可通过GPI结构锚定于细胞膜表面而不跨越其磷脂膜双层。将GPI与B7-1拼接直接整合于细胞表面，可克服基因转导法的诸多不便．为T细胞提供有利的共刺激信号，增强T细胞的抗肿瘤作用，诱导肿瘤免疫。现将其研究进展综述如下。     

CTLA-4及其衍生物和支气管哮喘

在过敏性哮喘的发病机制中,Th1/Th2亚群数目和（或）功能比例失衡是哮喘最重要的免疫学异常,其中CD4^＋T细胞在启动抗原特异性免疫应答过程中起重要作用,它的增殖活化需要两个刺激信号：第一信号（识别信号）由T细胞受体（TCR）与抗原提呈细胞（APC）提呈的MHC-抗原肽复合物相结合所产生,第二信号（共刺激信号）由APC表面的共刺激分子与T细胞表面对应受体分子相结合产生.目前认为CD28和CTLA-4是一对具有正负调节功能的重要共刺激分子,细胞毒性T细胞相关性抗原-4（CTLA-4）和CD28竞争性结合B7分子从而下调或终止T细胞反应.CTLA4-Ig能有效抑制哮喘动物模型的气道高反应性、肺部嗜酸粒细胞（EOS）增多等表现,使抗原导致的气道功能紊乱症状明显减轻.但研究表明,T细胞的活化存在非CD28依赖的途径,而且CTLA4-Ig阻断CD28/B7共刺激途径诱导的T细胞无能在一定条件下可以逆转,因此,CTLA4-Ig的单独使用价值有一定的局限性.CTLA4-FasL融合蛋白在体外能抑制混合淋巴细胞反应和诱导淋巴细胞凋亡效应,且作用比CTLA4-Ig和sFasL联合应用强.设想CTLA-4及其衍生物将为哮喘临床治疗提供广阔前景.本文就该问题作一综述.     

B7-1阻断剂对实验性小鼠支气管哮喘的治疗作用

支气管哮喘（简称哮喘）最重要的免疫学异常是Th1／Th2亚群数目和（或）功能比例失衡，表现为Th2亚群数目增多和功能亢进，Th1亚群数目减少和功能降低。抗原递呈细胞（APC）能刺激CD4^＋T淋巴细胞向Th2细胞分化，是诱导哮喘发病的第一步，APC／T淋巴细胞相互识别中，B7家族协同刺激信号和其配体的结合是诱导Th2效应的关键，分子中与哮喘关系最密切的是B7-1（CD80）和B7-2（CD56），其中B7-1／CD28是激活T淋巴细胞最重要的协同刺激通路是B7-1／CD28通路，其在哮喘的发病和治疗中具有重要研究价值。我们的实验以小鼠哮喘模型为研究对象，观察阻断B7-1／CD28协同刺激通路对哮喘的治疗作用，为探讨哮喘治疗的新途径提供实验资料。     

可诱导共刺激分子与自身免疫性疾病

自身免疫性疾病(autoimmune disease,AID)的发病机制非常复杂,但自身反应性T、B细胞的异常激活是AID发病过程中的一个必然环节,而T细胞的激活需要双信号作用,除T细胞受体与MHC分子-抗原肽复合物的特异性结合提供第一激活信号外,还需要CD28/B7等共刺激分子对提供第二激活信号.可诱导共刺激分子(inducible co-stimulator,ICOS)和可诱导共刺激分子配体(inducible co-stimulator ligand,I-COSL)是CD28家族和B7家族的新成员,     

CTLA4及其融合蛋白功能和应用的研究进展

细胞毒T淋巴细胞抗原4（CTLA4或CD152）是T细胞诱导外周免疫耐受的重要负性调节分子,主要表达于被激活的T细胞表面,是机体维持淋巴细胞稳态的关键因子。近期国内外均有文献显示CTLA4以其特异、低毒、高效的特点广泛应用于实验和临床治疗的各阶段。CTLA4融合蛋白作为CT-LA4的胞外结构域和人IgG1重链恒定区构建的重组融合蛋白,可以封闭抗原递呈细胞（APC）上的B7分子,阻断B7-     

Manipulation of costimulatory pathways in autoimmune diseases

There has recently been an increased understanding of the role of costimulatory pathways in the activation of the immune system and the maintenance of self-tolerance. It has been suggested that the absence of costimulatory molecules on normal tissue cells could serve to induce self-tolerance, and that inappropriate expression of costimulatory molecules on antigen-presenting cells (APCs) could activate self-reactive T cells, resulting in autoimmunity. Among several costimulatory molecules characterized, the interaction of CD28/CTLA4 on T cells with B7 (CD80 and CD86) on APC appears to be of primary importance. In fact, inhibition of the CD28–B7 interaction ameliorates several autoimmune diseases in experimental animal models. However, differential roles for CD80 and CD86 have been reported in certain conditions, and CTLA4 has been shown to play a negative role in T cell activation, suggesting that the actual regulatory mechanisms of this pathway in autoimmunity is much more complex. While the CD28–B7 interaction constitutes a predominant pathway of T cell costimulation, some intact T cell responses in CD28-deficient mice have suggested the presence of alternative pathways. T cell-dependent immunity is also critically regulated not only by other immunoglobulin superfamilies such as B7RP-1/ICOS, but also by tumor necrosis factor (TNF) and TNF-receptor superfamilies, which control immune responses in both a positive and a negative fashion. Therefore, further investigation of the physiological function of these costimulatory pathways in vivo may help in developing rational therapeutic approaches for autoimmune diseases.     

Manipulation of costimulatory pathways in autoimmune diseases

Abstract

There has recently been an increased understanding of the role of costimulatory pathways in the activation of the immune system and the maintenance of self-tolerance. It has been suggested that the absence of costimulatory molecules on normal tissue cells could serve to induce self-tolerance, and that inappropriate expression of costimulatory molecules on antigen-presenting cells (APCs) could activate self-reactive T cells, resulting in autoimmunity. Among several costimulatory molecules characterized, the interaction of CD28/CTLA4 on T cells with B7 (CD80 and CD86) on APC appears to be of primary importance. In fact, inhibition of the CD28–B7 interaction ameliorates several autoimmune diseases in experimental animal models. However, differential roles for CD80 and CD86 have been reported in certain conditions, and CTLA4 has been shown to play a negative role in T cell activation, suggesting that the actual regulatory mechanisms of this pathway in autoimmunity is much more complex. While the CD28–B7 interaction constitutes a predominant pathway of T cell costimulation, some intact T cell responses in CD28-deficient mice have suggested the presence of alternative pathways. T cell-dependent immunity is also critically regulated not only by other immunoglobulin superfamilies such as B7RP-1/ICOS, but also by tumor necrosis factor (TNF) and TNF-receptor superfamilies, which control immune responses in both a positive and a negative fashion. Therefore, further investigation of the physiological function of these costimulatory pathways in vivo may help in developing rational therapeutic approaches for autoimmune diseases.     

B7h is required for T cell activation, differentiation, and effector function

T helper (Th) cell activation, differentiation, and immune function are regulated by costimulatory molecules. Inducible costimulator (ICOS) is a recently identified costimulatory receptor expressed on activated T cells. A ligand for ICOS, B7h, is expressed on B cells and other types of antigen-presenting cells (APC). Although ICOS has been shown to be essential in T cell activation and differentiation, the regulatory roles of B7h at different stages of T cell immune responses have not been examined genetically. In this study, we generated and analyzed B7h-deficient mice. We present evidence that B7h is the only ligand for ICOS, and ICOS, its only corresponding receptor. Th cells, when activated with B7h-deficient APC, exhibited reduced proliferation and IL-2 production. In addition, Th cells produced significantly reduced amounts of IL-4 and -13 after differentiation at the presence of B7h-/- APC. This cytokine defect was associated with a deficiency in c-Maf expression and could be rescued completely by c-Maf overexpression in T cells. Furthermore, we showed that effector T cells, when restimulated in the presence of B7h-deficient APC, exhibited reduced Th2 cytokine production. Therefore, B7h is required for proper Th cell activation, differentiation, and effector cytokine expression.     

Costimulatory and coinhibitory molecules of B7-CD28 family in cardiovascular atherosclerosis: A review

Accumulating evidence supports the active involvement of vascular inflammation in atherosclerosis pathogenesis. Vascular inflammatory events within atherosclerotic plaques are predominated by innate antigen-presenting cells (APCs), including dendritic cells, macrophages, and adaptive immune cells such as T lymphocytes. The interaction between APCs and T cells is essential for the initiation and progression of vascular inflammation during atherosclerosis formation. B7-CD28 family members that provide either costimulatory or coinhibitory signals to T cells are important mediators of the cross-talk between APCs and T cells. The balance of different functional members of the B7-CD28 family shapes T cell responses during inflammation. Recent studies from both mouse and preclinical models have shown that targeting costimulatory molecules on APCs and T cells may be effective in treating vascular inflammatory diseases, especially atherosclerosis. In this review, we summarize recent advances in understanding how APC and T cells are involved in the pathogenesis of atherosclerosis by focusing on B7-CD28 family members and provide insight into the immunotherapeutic potential of targeting B7-CD28 family members in atherosclerosis.     

Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation.

The maximal T-cell response to its antigen requires presentation of the antigen by a major histocompatibility complex class II molecule as well as the delivery of one or more costimulatory signals provided by the antigen-presenting cell (APC). Although a number of candidate molecules have been identified that are capable of delivering a costimulatory signal, increasing evidence suggests that one such critical pathway involves the interaction of the T-cell surface antigen CD28 with its ligand B7, expressed on APCs. In view of the number of potential costimulatory molecules that might be expressed on the cell surface of APCs, artificial APCs were constructed by stable transfection of NIH 3T3 cells with HLA-DR7, B7, or both. Here, we show that in a human antigen-specific model system, when tetanus toxoid peptide antigen is presented by cells cotransfected with HLA-DR7 and B7, optimal T-cell proliferation and interleukin 2 production result. In contrast, antigen presentation, in the absence of B7 costimulation, results in T-cell clonal anergy. These results demonstrate that it is possible to induce antigen-specific clonal tolerance in human T cells that have been previously sensitized to antigen. The artificial antigen-presenting system provides a useful model for the investigation of the biochemical events involved in the generation of tolerance and for the study of signals necessary to overcome tolerance.     

Direct stimulation of naïve T cells by antigen-presenting cell vesicles

T cells are activated through T cell receptor (TCR) recognition of peptidic fragments of antigen bound to major histocompatibility complex (MHC) molecules on antigen-presenting cells (APC). In addition, T cells require a costimulatory signal delivered through contact with other ligands on APC, especially B7 and ICAM-1 which bind to CD28 and LFA-1, respectively, on T cells. Under physiological conditions, T cell activation requires contact with viable APC. Under defined conditions, however, T cells can be activated by exosomes secreted by APC. Evidence will be presented that exosomes can be directly immunogenic for CD8(+) T cells in the absence of normal APC with the proviso that exosomes express a high density of MHC I/peptide complexes as well as B7 and ICAM-1. Similar findings apply to plasma membrane fragments prepared from APC sonicates.     

Costimulation via lymphocyte function-associated antigen 1 in the absence of CD28 ligation promotes anergy of naive CD4+ T cells

The mechanisms controlling induction of anergy at the level of naive CD4+ T cells are poorly understood but thought to reflect limited contact with costimulatory molecules during T cell antigen receptor (TCR) ligation. To clarify this question, naive TCR transgenic CD4+ cells were exposed to specific peptide presented by transfected antigen-presenting cells (APC) expressing MHC class II molecules with defined accessory molecules. Significantly, culturing CD4(+) cells with APC expressing MHC II plus peptide alone elicited early TCR signaling but failed to induce either proliferation or anergy. Culture with APC expressing MHC II plus B7 molecules led to strong proliferation and T cell priming but no anergy. In marked contrast, conspicuous induction of anergy occurred after T cell culture with APC expressing MHC class II and intercellular adhesion molecule-1 (ICAM-1). Thus, at the level of naive CD4(+) cells, anergy induction appears to reflect selective contact with APC expressing ICAM-1 in the absence of B7.     

Mice expressing both B7-1 and viral glycoprotein on pancreatic beta cells along with glycoprotein-specific transgenic T cells develop diabetes due to a breakdown of T-lymphocyte unresponsiveness.

T lymphocytes have been implicated in the onset of many autoimmune diseases; however, the mechanisms underlying T-cell activation toward self antigens are poorly understood. To study whether T-lymphocyte costimulation can overcome the immunologic unresponsiveness observed in an in vivo model, we have created transgenic mice expressing the costimulatory mouse molecule B7-1, a ligand for the CD28 receptor, on pancreatic beta cells. We now report that triple-transgenic mice expressing both B7-1 and a viral glycoprotein on their beta cells, along with T cells expressing the viral-glycoprotein-specific transgenic T-cell receptor, all develop insulitis (lymphocytic infiltration of the pancreatic islets) and diabetes. In striking contrast, the T cells in double-transgenic mice expressing the same viral glycoprotein (but no B7) on their pancreatic beta cells and the transgenic T-cell receptor on their T cells, reported earlier, remain indifferent to the glycoprotein-expressing beta cells. In fact, all three transgenes are required to initiate immune-mediated destruction of the beta cells. Mice expressing any of the transgenes alone, or any two in combination, maintain normal islet architecture and never spontaneously develop insulitis or diabetes. Our results show that aberrant B7 expression on peripheral tissues may play an important role in the activation of self-reactive T cells and further suggest that abnormal expression of costimulatory receptors may be involved in various T-cell-mediated autoimmune diseases.     

Expression and functional significance of an additional ligand for CTLA-4.

Effective T-cell activation requires antigen/major histocompatibility complex engagement by the T-cell receptor complex in concert with one or more costimulatory molecules. Recent studies have suggested that the B7 molecule, expressed on most antigen presenting cells, functions as a costimulatory molecule through its interaction with CD28 on T cells. Blocking the CD28/B7 interaction with CTLA4Ig inhibits T-cell activation in vitro and induces unresponsiveness. We demonstrate that another molecule(s), termed B7-2, is expressed constitutively on dendritic cells, is differentially regulated on B cells, and costimulates naive T cells responding to alloantigen. B7-2 is up-regulated by lipopolysaccharide in < 6 hr and is maximally expressed on the majority of B cells by 24 hr. In contrast, B7 is detected only on a subset of activated B cells late (48 hr) after stimulation. In addition, Con A directly induces B7-2 but not B7 expression on B cells. Finally, although both anti-B7 monoclonal antibodies and CTLA4Ig blocked T-cell proliferation to antigen-expressing B7 transfectants, only CTLA4Ig had any significant inhibitory effect on T-cell proliferation to antigens expressed on natural antigen presenting cells, such as dendritic cells. Thus, B7 is not the only costimulatory molecule capable of initiating T-cell responses since a second ligand, B7-2, can provide a necessary second signal for T-cell activation.