T细胞共刺激信号系统研究进展

T细胞是获得性免疫应答的主要识别和效应细胞．T细胞的活化需要两种信号同时存在（即双信号模型，two-signal model）：一是由T细胞受体（TCR）与MHC-抗原肽复合物介导的第一信号，该信号决定了T细胞抗原应答的特异性；二是由表达于T细胞表面的膜蛋白分子及其配体介导的共刺激信号，该信号对于T细胞识别抗原后的完全活化是必须的．共刺激分子的发现为调控T细胞活化及其介导的免疫反应提供了新策略．     

CD28分子的研究进展

目前大量实验已证明,CD28家族分子与B7家族分子结合后产生的共刺激信号,即第二信号在免疫应答的T细胞激活中起重要作用.CD28与B7两种分子的相互作用可产生一个特殊的协同刺激使TCR介导的抗原识别信号导致细胞的活化而不是无能,现就CD28家族分子的结构、配体、信号传导以及对免疫应答的调控作一综述.     

Ⅰ型糖尿病基因免疫治疗研究

I型糖尿病是由T细胞介导自身免疫性疾病，由胰岛β细胞免疫破坏所致．其基因免疫治疗主要包括诱导免疫耐受、改变抗原提呈细胞的功能及活性、改变免疫调节细胞因子、干扰协同刺激信号和调节细胞凋亡．     

T细胞对不同配体的鉴别模型

T淋巴细胞对抗原多肽的免疫应答是免疫系统的重要事件,T细胞对于分辨不同的MHC－pep复合物有着不同寻常的能力,抗原多肽上信号氨基酸部分的细小判别,将有效的引起截然不同的T细胞响应,有些可以激活T细胞,而另外一些却抑制了细胞的活化,此模型深入考虑了PTK的活性及TCP与其配体的亲和力,将早期信号事件与决定了T细胞活化的持续信号联系了起来,为T细胞对不同配体的免疫应答提供了一个合理的理论解释。     

正常成人外周血全血培养激活T细胞表达活化抗原

目的：研究正常成人外周血T细胞体外活化表达活化抗原CD69，CD25及HLA－DR的规律与蛋白激酶C（PKC）抑制剂对此的影响。方法：健康志愿者（10名）外周血以佛波醇酯（PDB）＋离子霉素（lon)或植物血凝素（PHA）刺激不同时间后，经双荧光染色后获取有核细胞，以流式细胞仪测定CD3^ T细胞活化抗原CD69，CD25及LHA－DR的表达。结果：无论PDB＋Ion还是PHA均可刺激CD3^ T细胞表达CD25,24h后的表达率分别达57．5％和39．8％，以PDB＋Ion刺激4h，T细胞CD69表达已达90％以上，而此时CD25尚未表达，HLA－DR则在72h后表达明显上调，PKC抑制剂H7能完全抑制DB＋Ion引起的CD69及CD25上调，但仅部分抑制LA－DR的表达。结论：正常成人中血CD3^3 T细胞经多克隆活化剂刺激后CD69表达最快，最高，CD25次之，HLA－DR较慢较低；三者的表达均可被PKC抑制剂H7所抑制，表明PKC在3种活化抗原的表达中起重要作用。     

ITAM两步磷酸化基础上的TCR识别模型

将T细胞受体(TCR)的活性与免疫酪氨酸受体激活基序(ITAM)活性联系起来，深入考虑了TCR与其配体的亲和力和离解率．结果表明抗原多肽上信号氨基酸部分的细小差别，将有效地引起截然不同的T细胞应答反应．发生在T细胞应答早期信号事件中的TCR与其配体的亲和力和离解率参与决定了最终的T细胞应答结果．     

滤泡树状突细胞在HIV感染中的作用

滤泡树状突细胞是抗原提呈细胞[1]，它提呈抗原给B细胞和活化的T细胞起动免疫应答。HIV是引起艾滋病的病原体，它可以侵犯T细胞，造成细胞免疫功能极度低下产生艾滋病。滤泡树状突细胞可以提呈HIV-抗HIV复合物给活化的T细胞，使T细胞感染，机体发病。     

Ⅰ型糖尿病基因免疫治疗研究

Ⅰ型糖尿病是由T细胞介导自身免疫性疾病,由胰岛β细胞免疫破坏所致.其基因免疫治疗主要包括诱导免疫耐受、改变抗原提呈细胞的功能及活性、改变免疫调节细胞因子、干扰协同刺激信号和调节细胞凋亡.     

B7-TNFR嵌合分子的构建及其在真核细胞中的表达

Ｂ７－ＣＤ２８／ＣＴＬＡ－４共刺激旁路在免疫应答中的Ｔ细胞激活中有重要功能，Ｂ７分子的肿瘤基因疗法是目前肿瘤基因治疗的热点和方向。ＴＮＦα能通过ＴＮＦＲ诱导细胞凋亡，直接杀伤肿瘤细胞。构建了由共刺激分子Ｂ７－１的细胞外区与ＴＮＦＲ Ｉ的越膜区和细胞内区组成的嵌合分子Ｂ７－ＴＮＦＲ，并在细胞表面得到了表达。这种分子可能从２个方面达到肿瘤治疗的目的；（１）增强肿瘤细胞激活机体免疫系统的能力；（２）诱导     

去泛素化酶7与髓样分化因子88蛋白相互作用的研究

Toll-like受体（TLRs）介导的信号途径不仅参与机体识别病原微生物入侵、诱导免疫应答,而且还可诱导机体产生破坏性炎症反应．通过免疫共沉淀、免疫荧光共定位、间接免疫荧光等实验方法鉴定去泛素化酶7（USP7）和TLR信号途径中重要接头蛋白——髓样分化因子88（MyD88）的相互作用,结果表明USP7和MyD88可在细胞质中共定位并可发生相互作用．该研究对阐释TLR信号通路的机制奠定了重要的基础．     

ICOS is critical for CD40-mediated antibody class switching

The inducible co-stimulatory molecule (ICOS) is a CD28 homologue implicated in regulating T-cell differentiation. Because co-stimulatory signals are critical for regulating T-cell activation, an understanding of co-stimulatory signals may enable the design of rational therapies for immune-mediated diseases. According to the two-signal model for T-cell activation, T cells require an antigen-specific signal and a second, co-stimulatory, signal for optimal T-cell activation. The co-stimulatory signal promotes T-cell proliferation, lymphokine secretion and effector function. The B7-CD28 pathway provides essential signals for T-cell activation, but does not account for all co-stimulation. We have generated mice lacking ICOS (ICOS-/- ) to determine the essential functions of ICOS. Here we report that ICOS-/- mice exhibit profound deficits in immunoglobulin isotype class switching, accompanied by impaired germinal centre formation. Class switching was restored in ICOS-/- mice by CD40 stimulation, showing that ICOS promotes T-cell/B-cell collaboration through the CD40/CD40L pathway.     

Cbl-b regulates the CD28 dependence of T-cell activation

Whereas co-stimulation of the T-cell antigen receptor (TCR) and CD28 triggers T-cell activation, stimulation of the TCR alone may result in an anergic state or T-cell deletion, both possible mechanisms of tolerance induction. Here we show that T cells that are deficient in the adaptor molecule Cbl-b (ref. 3) do not require CD28 engagement for interleukin-2 production, and that the Cbl-b-null mutation (Cbl-b(-/-)) fully restores T-cell-dependent antibody responses in CD28-/- mice. The main TCR signalling pathways, such as tyrosine kinases Zap-70 and Lck, Ras/mitogen-activated kinases, phospholipase Cgamma-1 and Ca2+ mobilization, were not affected in Cbl-b(-/-) T cells. In contrast, the activation of Vav, a guanine nucleotide exchange factor for Rac1/Rho/CDC42, was significantly enhanced. Our findings indicate that Cbl-b may influence the CD28 dependence of T-cell activation by selectively suppressing TCR-mediated Vav activation. Mice deficient in Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis, suggesting that the dysregulation of signalling pathways modulated by Cbl-b may also contribute to human autoimmune diseases such as multiple sclerosis.     

T-cell co-stimulation through B7RP-1 and ICOS

T-cell activation requires co-stimulation through receptors such as CD28 and antigen-specific signalling through the T-cell antigen receptor. Here we describe a new murine costimulatory receptor-ligand pair. The receptor, which is related to CD28 and is the homologue of the human protein ICOS, is expressed on activated T cells and resting memory T cells. The ligand, which has homology to B7 molecules and is called B7-related protein-1 (B7RP-1), is expressed on B cells and macrophages. ICOS and B7RP-I do not interact with proteins in the CD28-B7 pathway, and B7RP-1 co-stimulates T cells in vitro independently of CD28. Transgenic mice expressing a B7RP-1-Fc fusion protein show lymphoid hyperplasia in the spleen, lymph nodes and Peyer's patches. Presensitized mice treated with B7RP-1-Fc during antigen challenge show enhanced hypersensitivity. Therefore, B7RP-1 exhibits co-stimulatory activities in vitro and in vivo. ICOS and B7RP-1 define a new and distinct receptor-ligand pair that is structurally related to CD28-B7 and is involved in the adaptive immune response.     

Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b

The signalling thresholds of antigen receptors and co-stimulatory receptors determine immunity or tolerance to self molecules. Changes in co-stimulatory pathways can lead to enhanced activation of lymphocytes and autoimmunity, or the induction of clonal anergy. The molecular mechanisms that maintain immunotolerance in vivo and integrate co-stimulatory signals with antigen receptor signals in T and B lymphocytes are poorly understood. Members of the Cbl/Sli family of molecular adaptors function downstream from growth factor and antigen receptors. Here we show that gene-targeted mice lacking the adaptor Cbl-b develop spontaneous autoimmunity characterized by auto-antibody production, infiltration of activated T and B lymphocytes into multiple organs, and parenchymal damage. Resting cbl-b(-/-) lymphocytes hyperproliferate upon antigen receptor stimulation, and cbl-b(-/-) T cells display specific hyperproduction of the T-cell growth factor interleukin-2, but not interferon-gamma or tumour necrosis factor-alpha. Mutation of Cbl-b uncouples T-cell proliferation, interleukin-2 production and phosphorylation of the GDP/GTP exchange factor Vav1 from the requirement for CD28 co-stimulation. Cbl-b is thus a key regulator of activation thresholds in mature lymphocytes and immunological tolerance and autoimmunity.     

Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut

The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.     

基于免疫危险理论的手机恶意软件检测模型

为了提高智能手机恶意软件检测的自适应性和有效性,该文提出了基于免疫危险理论的手机恶意软件检测模型,该模型由4个部分组成:数据采集、危险信号生成、共刺激信号生成和预警部分,针对不同的恶意软件,采用微分方法表达危险信号,由自适应抗原提呈细胞产生相应的共刺激信号,最后对恶意软件产生预警.通过实验验证了该文模型的自适应性和有效性.     

Characterization of murine cytolytic-helper hybrid T cell clones

L3T4, Lyt-2 and the T-cell receptor for antigen are cell-surface molecules involved in antigen specific T cell activation. We have constructed functional murine cytolytic-helper T-cell hybrid clones to study the link between expression of cell-surface molecules and specific cell function. Three of the clones express two antigen receptors and both Lyt-2 and L3T4, normally expressed on mutually exclusive subsets of mature T lymphocytes. The pattern of lymphokines produced by the hybrid cells in response to antigen was not controlled by the specific antigen receptor; both T-cell growth factor, produced only by the helper T-cell partner, and gamma-interferon, produced only by the cytolytic T-cell partner, were secreted when either antigen receptor was stimulated. However, cytolytic activity appeared to be restricted to the recognition of antigen by the T-cell receptor of the cytolytic partner. Thus cytolysis appears to be rightly linked to the antigen receptor of the cytolytic parent but lymphokine release is not tightly linked.     

Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice

Rheumatoid arthritis (RA), which afflicts about 1% of the world population, is a chronic systemic inflammatory disease of unknown aetiology that primarily affects the synovial membranes of multiple joints. Although CD4(+) T cells seem to be the prime mediators of RA, it remains unclear how arthritogenic CD4(+) T cells are generated and activated. Given that highly self-reactive T-cell clones are deleted during normal T-cell development in the thymus, abnormality in T-cell selection has been suspected as one cause of autoimmune disease. Here we show that a spontaneous point mutation of the gene encoding an SH2 domain of ZAP-70, a key signal transduction molecule in T cells, causes chronic autoimmune arthritis in mice that resembles human RA in many aspects. Altered signal transduction from T-cell antigen receptor through the aberrant ZAP-70 changes the thresholds of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might also be crucial to the development of disease in a subset of patients with RA.     

The dynamics of CD4+ T-cell depletion in HIV disease

The size and composition of the CD4+ T-cell population is regulated by balanced proliferation of progenitor cells and death of mature progeny. After infection with the human immunodeficiency virus, this homeostasis is often disturbed and CD4+ T cells are instead depleted. Such depletion cannot result simply from accelerated destruction of mature CD4+ T cells - sources of T-cell production must also fail. Ironically, this failure may be precipitated by physiological mechanisms designed to maintain homeostasis in the face of accelerated T-cell loss.     

Stimulation of the phosphatidylinositol pathway can induce T-cell activation

The T-cell antigen receptor (TCR) regulates two signal transduction pathways: the phosphatidylinositol (PtdIns) and tyrosine kinase pathways. Stimulation of T cells with antigen or anti-TCR monoclonal antibodies induces an increase in inositol phosphates and diacylglycerol, the second messengers responsible for the mobilization of cytoplasmic free calcium and activation of protein kinase C-4. The TCR also activates a tyrosine kinase that is not intrinsic to the TCR. The relationship between these two signal transduction pathways and their contribution to later T-cell responses is unclear. Studies using variants of a murine hybridoma suggested that the PtdIns pathway might not be necessary for or be involved in regulating interleukin-2 (IL-2) production. To address the relationship between later T-cell responses and the early biochemical signals, we investigated the ability of a heterologous receptor with defined signal transduction function to induce T-cell activation. The human muscarinic subtype-1 receptor (HM1), which elicits PtdIns metabolism in neuronal cells through a G protein-coupled mechanism, also functionally activates this pathway when expressed in the T-cell line Jurkat-derived host, J-HM1-2.2 (ref.8). We show here that stimulation of HM1 alone induced IL-2 production and IL-2 receptor alpha chain expression. HM1 does not induce the tyrosine kinase pathway, suggesting that this pathway does not directly influence later T cell-activation responses. Instead, our studies indicate that activation of the PtdIns pathway is probably sufficient to induce later T-cell responses.