B7家族成员的研究新进展

B7分子属免疫球蛋白超家族成员,表达于多种免疫细胞和非免疫细胞上.抗原提呈细胞表面的B7分子与T细胞上的相应受体结合可提供T细胞活化的第二信号,从而调节和控制T细胞的活化、增殖及免疫应答.B7家族成员在感染、肿瘤以及自身免疫性疾病等发病机制中起着关键作用.选择性阻断协同刺激分子有望能成为临床治疗这些疾病的一种新途径.近...     

Regulating the regulators: costimulatory signals control the homeostasis and function of regulatory T cells

Summary:  Costimulation is a concept that goes back to the early 1980s when Lafferty and others hypothesized that cell surface and soluble molecules must exist that are essential for initiating immune responses subsequent to antigen exposure. The explosion in this field of research ensued as over a dozen molecules have been identified to function as second signals following T-cell receptor engagement. By 1994, it seemed clear that the most prominent costimulatory pathway CD28 and functionally related costimulatory molecules, such as CD154, were the major drivers of a positive immune response. Then the immunology world turned upside down. CD28 knockout mice, which were, in most cases, immunodeficient, led to increased autoimmunity when bred into the non-obese diabetic background. Another CD28 family member, cytotoxic T-lymphocyte-associated protein 4, which was presumed to be a costimulatory molecule on activated T cells, turned out to be critical in downregulating immunity. These results, coupled with the vast suppressor cell literature which had been largely rebuked, suggested that the immune system was not poised for response but controlled in such a way that regulation was dominant. Over the last decade, we have learned that these costimulatory molecules play a key role in the now classical CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) that provide critical control of unwanted autoimmune responses. In this review, we discuss the connections between costimulation and Tregs that have changed the costimulation paradigm.     

Molecular mechanism and function of CD40/CD40L engagement in the immune system

Summary:  During the generation of a successful adaptive immune response, multiple molecular signals are required. A primary signal is the binding of cognate antigen to an antigen receptor expressed by T and B lymphocytes. Multiple secondary signals involve the engagement of costimulatory molecules expressed by T and B lymphocytes with their respective ligands. Because of its essential role in immunity, one of the best characterized of the costimulatory molecules is the receptor CD40. This receptor, a member of the tumor necrosis factor receptor family, is expressed by B cells, professional antigen-presenting cells, as well as non-immune cells and tumors. CD40 binds its ligand CD40L, which is transiently expressed on T cells and other non-immune cells under inflammatory conditions. A wide spectrum of molecular and cellular processes is regulated by CD40 engagement including the initiation and progression of cellular and humoral adaptive immunity. In this review, we describe the downstream signaling pathways initiated by CD40 and overview how CD40 engagement or antagonism modulates humoral and cellular immunity. Lastly, we discuss the role of CD40 as a target in harnessing anti-tumor immunity. This review underscores the essential role CD40 plays in adaptive immunity.     

CD28 Function: A Balance of Costimulatory and Regulatory Signals

Both the recognition of MHC/antigen complex by the T-cell receptor and engagement of costimulatory molecules are necessary for efficient T-cell activation. CD28 has been widely recognized as the major costimulation pathway for naive T-cell activation, and the CD28/B7 pathway plays a central role in immune responses against pathogens, autoimmune diseases, and graft rejection. In this review, we will summarize evidence that CD28 is also prominent in the regulation of immune responses and the maintenance of peripheral tolerance. Indeed, CD28 engagement increases the expression of the down-modulatory molecule CTLA-4, induces the differentiation of Th2 cells that have a protective function in autoimmunity, and has an obligatory role in the homeostasis of regulatory T cells. Therefore, CD28/B7 interactions induce a balance of costimulatory and regulatory signals that have opposite outcomes on immune responses. This new perspective on CD28 function suggests that caution should be taken in the development of immunotherapies targeting costimulatory pathways.     

The capacity of the TNF family members 4-1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells

Activating signals generated by members of the tumour necrosis factor receptor superfamily upon interaction with their cognate ligands play important roles in T-cell responses. Members of the tumour necrosis factor family namely 4-1BBL, OX40L, CD70, GITRL, LIGHT and CD30L have been described to function as costimulatory molecules by binding such receptors on T cells. Using our recently described system of T-cell stimulator cells we have performed the first study where all these molecules have been assessed and compared regarding their capacity to costimulate proliferation and cytokine production of human T cells. 4-1BBL, which we found to be the most potent molecule in this group, was able to mediate sustained activation and proliferation of human T cells. OX40L and CD70 were also strong inducers of T-cell proliferation, whereas the costimulatory capacity of human GITRL was significantly lower. Importantly CD30L and LIGHT consistently failed to act costimulatory on human T cells, and we therefore suggest that these molecules might be functionally distinct from the costimulatory members of this family.     

The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function

Upon encounter with specific antigen, na?veT helper precursor (THP) cells become activated. This event is regulated not only by engagement of the T cell receptor (TCR) with peptide presented in the context of major histocompatibility complex (MHC) class II molecules but by a number of costimulatory signals. CD28 engagement by B7-1 and B7-2 on resting THP cells provides a critical signal for initial cell cycle progression, interleukin 2 production and clonal expansion. However, largely as a consequence of the unraveling of the human genome, it is becoming clear that B7-1 and B7-2 are part of a larger family T of related counter-receptors that play an essential role in regulating the fate of primed, rather then resting,THP cells. These molecules play an important sequential role and act, together with B7-1- and B7-2-primed T cells, in the acquisition of effector function and/or tolerance induction.     

Role of B7 costimulatory molecules in immune responses and T-helper cell differentiation in response to recombinant HagB from Porphyromonas gingivalis

In addition to antigen-specific signals mediated through the T-cell receptor, T cells also require antigen nonspecific costimulation for activation. The B7 family of molecules on antigen-presenting cells, which include B7-1 (CD80) and B7-2 (CD86), play important roles in providing costimulatory signals required for development of antigen-specific immune responses. Hemagglutinin B (HagB) is a nonfimbrial adhesin of the periodontopathic microorganism Porphyromonas gingivalis and is thought to be involved in the attachment of the bacterium to host tissues. However, the immune mechanisms involved in responses to HagB and their roles in pathogenesis have yet to be elucidated. Therefore, the purpose of this study was to determine the role of B7 costimulatory molecules on T-helper-cell differentiation for the induction of immune responses to HagB. Mice deficient in either or both of the costimulatory molecules B7-1 and B7-2 were used to explore their role in immune responses to HagB after subcutaneous immunization. B7-1(-/-) mice had levels of immunoglobulin G (IgG) anti-HagB antibody activity in serum similar to those of wild-type mice, whereas lower serum IgG anti-HagB antibody responses were seen in B7-2(-/-) mice. Moreover, significantly lower numbers of IgG antibody-secreting cells and lower levels of CD4(+)-T-cell proliferation were observed in B7-2(-/-) mice compared to wild-type mice. No serum IgG response to HagB was detected in B7-1/B7-2(-/-) mice. Analysis of the subclass of the serum IgG responses and the cytokines induced in response to HagB revealed that B7-2(-/-) mice had significantly lower IgG1 and higher IgG2a anti-HagB antibody responses compared to wild-type mice. The B7-2(-/-) mice also had significantly reduced levels of interleukin-4 (IL-4) and IL-5 and enhanced level of gamma interferon. Furthermore, assessment of B7-1 and B7-2 expression on B cells and macrophages derived from wild-type BALB/c mice after in vitro stimulation with HagB revealed a predominant upregulation in the expression of the B7-2 costimulatory molecule on B cells and macrophages. Essentially no change was seen in the expression of B7-1. Taken together, these results suggest a critical role for B7, especially B7-2, for the preferential induction of a Th2-like response to HagB.     

REVIEW ARTICLE: B7 Family Molecules as Regulators of the Maternal Immune System in Pregnancy

Citation Petroff MG, Perchellet A. B7 family molecules as regulators of the maternal immune system in pregnancy. Am J Reprod Immunol 2010 Placental and fetal growth and development are associated with chronic exposure of the maternal immune system to fetally derived, paternally inherited antigens. Because maternal lymphocytes are aware of fetal antigens, active tolerance mechanisms are required to ensure unperturbed progression of pregnancy and delivery of a healthy newborn. These mechanisms of tolerance may include deletion, receptor downregulation, and anergy of fetal antigen‐specific cells in lymphoid tissues, as well as regulation at the maternal–fetal interface by a variety of locally expressed immunoregulatory molecules. The B7 family of costimulatory molecules comprises one group of immunoregulatory molecules present in the decidua and placenta. B7 family members mediate both inhibitory and stimulatory effects on T‐cell activation and effector functions and may play a critical role in maintaining tolerance to the fetus. Here, we review the known functions of the B7 family proteins in pregnancy.     

Costimulatory pathways in transplantation: challenges and new developments

Summary:  T cells are central to graft rejection, and therefore preventing T cells from recognizing and destroying allografts remains an important area of transplant research. However, T cells are also required for transplant tolerance; a subset can enforce a state of tolerance by functioning as regulatory cells. As both rejection and regulation directed against alloantigens require T-cell activation, costimulatory molecules undoubtedly play an important role in regulating both processes and ultimately the fate of the allograft. However, costimulation involves an incredibly complex array of interactions that may act contemporaneously or at different times; these interactions can have additive or opposing effects on T-cell activation or differentiation. While some costimulatory molecules mediate activation of naive T cells or generation of memory T cells, others inhibit T-cell activation and promote anergy or apoptosis. Moreover, a given pathway can have diametrically different effects on T-effector cells and regulatory T cells (Tregs). Such a complexity presents both challenges and opportunities in targeting T-cell costimulatory pathways to promote transplant tolerance. In this review article, we provide a summary of recent advances in our understanding of T-cell costimulatory pathways in regulating different phases of the T-cell response in transplant models. We focus specifically on costimulatory molecules in the immunoglobulin (Ig) superfamily, tumor necrosis factor (TNF)/TNF receptor superfamily, and in the emerging T-cell Ig domain and mucin domain family (TIM), highlighting their unique and redundant roles in regulating the T-effector and Treg responses after transplantation. Finally, we summarize emerging approaches toward inducing tolerance by tipping the balance between cytopathic T-effector cells and protective Tregs by selectively targeting specific T-cell costimulatory pathways that are critically involved.     

特发性血小板减少性紫癜共刺激分子表达的研究进展

特发性血小板减少性紫癜（ITP）是一种自身免疫性疾病,其发病机制尚未完全明确,目前已证实,ITP患者体内存在T、B淋巴细胞的异常活化和B淋巴细胞依赖Th细胞辅助而产生自身抗血小板抗体。在T、B淋巴细胞相互作用和产生自身抗体的病理过程中,CD80、CD86与其配体CD28、CTLA4结合及CD40与其配体CD40L相互作用提供的共刺激信号起了重要的作用。研究表明共刺激分子过度表达有可能激活自身反应性T淋巴细胞,导致自身免疫病的发生。     

Topical CTLA4-Ig suppresses ongoing mucosal immune response in presensitized murine model of allergic rhinitis.

Allergic rhinitis is thought to be mediated by CD4+ T cells producing Th2-associated cytokines. Optimal Ag-specific T-cell activation requires the engagement of T-cell receptor with antigen (Ag) in the context of MHC, and the engagement of appropriate costimulatory molecules. One of the most well-characterized costimulatory pathways is the interaction of B7/CD28-CTLA4 molecules. Recent studies have suggested that the costimulatory pathway may influence the development of Th2 immune responses. The objective of this study was the examination of the role of B7/CD28-CTLA4 costimulatory pathway in the pathogenesis of ovalbumin (OVA)-induced immune response in presensitized murine model of allergic rhinitis. Systemically presensitized BALB/c mice significantly developed Ag-induced early phase nasal symptoms, nasal hyperresponsiveness to histamine, nasal eosinophilia, serum levels of OVA- specific IgE and Th2-associated cytokines following repeated topical Ag challenges. Topical administration of CTLA4-Ig during nasal challenges inhibited Ag-induced nasal symptoms and histamine hyperresponsiveness. We also found a significant reduction in nasal lavage eosinophilia and serum levels of OVA-specific IgE. Furthermore, CTLA4-Ig treatment significantly decreased interleukin (IL)-4 content in nasal tissue, while there was no significant change in IL-5 or IFN-gamma levels. These results suggest that B7/CD28-CTLA4 costimulatory pathway mediates the development of ongoing Th2 immune responses and plays a major role in regulating allergic disease, such as allergic rhinitis.     

Costimulation by CD28 sFv expressed on the tumor cell surface or as a soluble bispecific molecule targeted to the L6 carcinoma antigen

Interaction of the CD80 (B7-1) and CD86 (B7-2) molecules on antigen presenting cells with the receptors CD28 and CTLA-4 on T cells generates signals important in the regulation of immune responses. Because this receptor system involves multiple receptor-ligand interactions, determining the function for individual receptors has been difficult. One approach is the use of antibodies and their derivatives with singular specificity as substitute ligands to explore the activities of these molecules. We have constructed recombinant mono-and bi-specific sFv molecules specific for the CD28 receptor that are capable of binding and generating costimulatory signals to activate T cells. We demonstrate that these soluble molecules are capable of higher levels of costimulation than soluble CD80Ig at equivalent concentrations. We also constructed artificial adhesion receptors on the cell surface using two different CD28-specific sFvIgs fused to the CD80 cytoplasmic and transmembrane domains. In this report, we compared costimulation by a soluble bispecific (αCD28-α6) single chain sFvIg fusion protein to that generated by L6 antigen positive (L6+) H3347 tumor cells transduced with cell surface expressed forms of aCD28 sFv's. We show that the bispecific protein can target potent CD28 costimulatory activity to L6+ tumor cells in vitro . We also show that transfection of the cell surface forms of the two different CD28 sFvIgs into H3347 tumor cells allows them to generate significant costimulatory signals to activated T cells. Finally, we demonstrate that tumor cell presentation of either the soluble bispecific or transduced cell surface sFv generate similar costimulatory effects resulting in T cell activation.     

T-cell costimulatory pathways in allograft rejection and tolerance

Summary: The destiny of activated T cells is critical to the ultimate fate of immune response. After encountering antigen, naïve T cells receive signal 1 through the T‐cell receptor (TCR)‐major histocompatibility complex (MHC) plus antigenic peptide complex and signal 2 through ‘positive’ costimulatory molecules leading to full activation. ‘Negative’ T‐cell costimulatory pathways, on the other hand, function to downregulate immune responses. The purpose of this article is to review the current state of knowledge and recent advances in our understanding of the functions of the positive and negative T‐cell costimulatory pathways in alloimmune responses. Specifically, we discuss the functions of the CD28:B7 and the tumor necrosis factor receptor (TNFR):tumor necrosis factor (TNF) family of molecules in allograft rejection and tolerance. We address the following important questions: are T‐cell costimulatory pathways merely redundant or do they provide distinct and unique functions? What are the important and unique interactions between the various pathways? And, what are the effects and mechanisms of targeting of these pathways in different types and patterns of allograft rejection and tolerance models?     

CD80, but not CD86 were up-regulated on the spleen-derived dendritic cells from OVA-sensitized and challenged BALB/c mice

Allergen-specific CD4+ T-helper (Th) 2 cells are involved in the induction and effector phase of allergic asthma. It is well established that T cells activation requires interaction of T cell receptor (TCR) and MHC-peptide complex, as well as costimulatory signal delivered by antigen presenting cells (APCs). There is increasing evidence that CD80 (B7.1) and CD86 (B7.2), as the most important costimulatory molecules, are involved in the allergic immune responses. In the present study, we investigated the CD80 and CD86 expression of spleen-derived dendritic cells (DCs) in a murine model of allergic asthma. We first established a murine model of ovalbumin (OVA)-allergic asthma that showed unique histological characteristic of allergic inflammation in the lung, high serum OVA-specific IgE level, high numbers of eosinophils in the bronchoalveolar lavage (BAL) and high production of Type 2 cytokines in the splenic T cells. In this model, we found that CD80 were significantly upregulated on the spleen-derived DCs from OVA-sensitized and challenged mice compared with that from PBS-treated or non-treated mice, while CD86 is not different among three groups. Furthermore, we demonstrated that Th2 immune responses were elicited by these DCs with high expression of CD80, even to nai;ve T cells from non-treated mice. Our results suggest that DCs in the spleen of allergic mice, via upregulation of CD80 might play a pivotal role in the maintenance and amplification of allergic immune response, namely Th2 immune response.     

Expression and function of the costimulatory molecule B7 on murine Langerhans cells: Evidence for an alternative CTLA-4 ligand

We have previously shown, through transfection experiments, that the murine B7 (mB7) molecule, a ligand for the CD28 and CTLA-4 receptors, is a sufficient costimulatory signal for the antigen-specific and major histocompatibility complex (MHC)-restricted activation of murine CD4⁺ T lymphocytes. In addition to mB7, another ligand with affinity for CTLA-4 has been described on spleen cells. Here we report our studies on the expression and function of these molecules on murine Langerhans cells (LC). Both anti-mB7 monoclonal antibody (mAb) 16-10A1 and human CTLA4Ig (hCTLA4Ig), a chimeric fusion protein consisting of the extracellular domain of human CLTA-4 and the constant domain of human IgG1, detected antigens(s) on cultured but not freshly isolated LC. Preincubation of cultured LC with anti-mB7 mAb did not significantly affect binding of hCTLA4Ig to these cells. This result demonstrate the existence of at least one other ligand for the CLTA-4 receptor on cultured LC. Functional studies revealed that the costimulatory activity of LC was inhibited better by hCTLA4Ig than by the anti-mB7 mAb. This differential effect was seen in the case of both alloreactive and antigen-specific, syngeneic T cell responses. These findings suggest that the non-mB7-ligand for CTLA-4 is functional and participates in the induction of immune responses by LC. Importantly, even synergistic combinations of anti-mB7 mAb and hCTLA4Ig did not inhibit completely the activity of LC. These findings therefore raise the possibility that LC express other costimulatory ligands besides mB7 and related family members.     

The balance of immune responses: costimulation verse coinhibition

Many of the B7 superfamily members (e.g., B7-1, B7-2, ICOS-L, B7-H1, B7-DC) were initially characterized as T cell costimulatory molecules. However, more recently it has become clear they can also coinhibit T cell responses. We review many of the B7 family members, with a particular focus on B7-H1, and examine their role in autoimmunity, transplant rejection, and cancer pathogenesis. It is crucial to understand that many B7 family members have opposing effects on an immune response. This cautions against using clinical immunotherapeutic reagents targeted against these molecules until we gain a better understanding of the circumstances that regulate the outcomes of the T cell response.     

调节性T细胞免疫效应的调节机制

调节性T细胞(regulatory T cell, Treg)在器官移植、过敏性疾病、肿瘤免疫、感染免疫等病理过程中具有重要作用。Treg通过复杂的作用机制维持外周免疫耐受,限制效应细胞的应答程度,从而防止过度免疫反应所致组织损伤。机体对Treg细胞免疫活性的调节作用及其机制主要包括细胞因子、树突状细胞及共刺激分子、Toll样受体调节机制。     

ERMAP is a B7 family-related molecule that negatively regulates T cell and macrophage responses

T cell activation and tolerance are tightly regulated by costimulatory and coinhibitory molecules. B7 family members play a crucial role in regulating immune responses. In this study, we identified erythroid membrane-associated protein (ERMAP) as a novel T cell inhibitory molecule. ERMAP shares significant sequence and structural homology with existing B7 family members in its extracellular domain. The ERMAP protein is expressed on the cell surface of resting and activated antigen-presenting cells (APCs) and in some tumor tissues. The putative ERMAP receptor is expressed on activated CD4 and CD8 T cells and macrophages. Both mouse and human ERMAP-IgG2a Fc (ERMAP-Ig) fusion proteins inhibit T cell functions in vitro. Administration of ERMAP-Ig protein ameliorates autoimmune diseases, including experimental autoimmune encephalomyelitis and type 1 diabetes, in mice. Anti-ERMAP antibody enhances macrophage phagocytosis of cancer cells in vitro. Furthermore, administration of an anti-ERMAP antibody inhibits tumor growth in mice likely by blocking the inhibitory effects of ERMAP on T cells and macrophages. Our results suggest that therapeutic interaction with the ERMAP inhibitory pathway may represent a novel strategy for treating patients with autoimmune disease or cancer.     

Role of costimulatory pathways in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis is an immune-mediated disorder of the central nervous system. T lymphocytes are thought to play a central role in the initiation and potentially in the propagation of this disease. Two signals are required for T-cell activation. The first signal consists of the interaction of the T-cell receptor with antigen presented by the MHC molecule on antigen-presenting cells. The second signal requires engagement of costimulatory receptors on T cells with their ligands on antigen-presenting cells. Several costimulatory pathways have been shown to play an important role in T-lymphocyte activation. Here we will review the current literature on the contribution of the B7-1/2-CD28/CTLA-4, inducible costimulatory molecule-B7h, programmed death pathway 1-programmed death pathway ligand 1/ligand 2, CD40-CD154, OX40-OX40 ligand, and CD137-CD137 ligand pathways to the pathogenesis of multiple sclerosis and their potential roles as therapeutic targets.     

B7-1-HSA (CD80-CD24), a recombinant hybrid costimulatory molecule retains ligand binding and costimulatory functions

Optimal activation of na?ve T lymphocyte requires two signals; an antigen-specific signal initiated by engagement of TCR with the antigen-MHC complex and a costimulatory signal independent of the antigen receptor complex. Without the costimulatory signal, T cells become anergic. Various adhesion molecules, such as B7-1 (CD80) and heat stable antigen (HSA, CD24), expressed on antigen presenting cells have been demonstrated to provide costimulatory signals to T cells. It was reported that the combinations of different adhesion molecules could induce even stronger immune response. In this study, we made a hybrid costimulatory molecule, B7-1-HSA, and tested its T cell stimulatory function. Chinese hamster ovary (CHO) cells expressing this hybrid molecule bound both anti-CD80 and anti-CD24 monoclonal antibodies, and induced stronger T cell proliferation than CHO cells expressing B7-1 or HSA alone. These results suggest that the B7-1-HSA hybrid molecule can deliver two costimulatory signals simultaneously that can synergize in inducing T cell proliferation. The purified B7-1-HSA protein reacted with both anti-B7-1 and anti-HSA mAbs in Western blotting and specifically mediated adhesion of Jurkat cells. Furthermore, purified B7-1-HSA molecule spontaneously incorporated onto cell membrane through its glycolipid anchor suggesting that this hybrid costimulatory molecule can be used in protein transfer to develop effective cancer vaccines.