T细胞免疫在抗结核杆菌感染中的研究进展

结核分枝杆菌是引起结核病的病原体,该细菌可侵犯全身各组织器官。结核病是一种慢性传染性疾病,具有持久性特点。该细菌为胞内寄生菌,特异性免疫以细胞免疫为主,主要包括CD4+T细胞免疫和CD8+T细胞免疫。结核分枝杆菌特异性免疫应答的特点之一是感染早期T细胞免疫应答延迟。其机制与结核杆菌抑制免疫细胞(CD4+和CD8+T细胞及DC)凋亡延迟应答,通过特异性Treg细胞抑制作用延迟应答以及结核杆菌慢性感染期间存在IFN-γ信号调节网络和ESAT-6抗原的慢性刺激作用有关,以此可调节和维持免疫应答。深入了解抗原特异性T细胞特异性免疫应答的机制,有益于抗结核疫苗的研制,为临床工作提供理论依据和科学方法。     

结核杆菌感染T细胞介导免疫应答研究的新进展

结核病对免疫学家构成了巨大的挑战,因为它是一种慢性传染性疾病,病原体具有持久性特点.在对人和动物进行实验时,检测到结核分枝杆菌适应性免疫应答的特点之一为感染早期T细胞免疫应答延迟.新近研究揭示了此种延迟应答的机制:通过结核杆菌抑制免疫细胞(CD4+和CD8+T细胞及DC)凋亡延迟应答,通过特异性Treg细胞抑制作用延迟应答.结核杆菌慢性感染期间存在IFNγ信号调节网络和ESAT-6抗原的慢性刺激作用,抗原特异性PD-1+ CD4+T细胞具有高度增殖分化为更多终末效应性T细胞的潜能,以此可调节和维持免疫应答.深入了解抗原特异性T细胞调节与维持适应性免疫应答的机制,有益于抗结核疫苗的设计和研制.     

分枝杆菌干扰抗原呈递细胞功能的研究进展

结核分枝杆菌(Mycobacterium tuberculosis,Mtb)为巨噬细胞内寄生菌,诱导宿主产生的免疫应答以细胞免疫应答为主,其中活化的T细胞特别是CD4 T辅助细胞(Th)及其激活调节的巨噬细胞等多种细胞所发挥的免疫机制是机体抗Mtb特异性免疫的关键,决定了胞内Mtb是被清除、还是进一步繁殖并发展为活动性结核抑或静止于胞内处于潜伏状态[1].     

保护HLA—DR3转基因鼠抗结核杆菌感染的复合期多表位疫苗

结核分枝杆菌（Mtb）每年导致近200万人死亡。BCG是当前唯一使用的结核病疫苗,能够诱导不恒定的保护力,不能防止潜伏性结核病的复活。因此,急切需要有效的疫苗来补充BCG。由于在细菌的繁殖阶段与休眠阶段结核分枝杆菌的蛋白质组在性质和数量上不同,所以改良的结核病疫苗应该能够诱导产生对感染各个阶段表达的结核分枝杆菌抗原的免疫应答。因此,这种“复合期”疫苗应该由结核分枝杆菌感染不同阶段表达的（免疫决定簇）抗原组成。作为一个概念性多级疫苗,我们通过融合五种HLA—DR3限制性T细胞表位构建了一个多表位肽（polyepitope）,这些限制性表位来源于不同的结核分枝杆菌蛋白,有繁殖期高表达产物（Ag85B,hsp65,19kDa脂蛋白）,有休眠菌富表达而且经结核菌素皮下测试阳性（TST＋）个体验证的产物（hspl6,Rvl733c）。在体外试验中,结核病治愈后HIA-DR3＋而非HLA-DR3-病人和结核菌素皮下测试阳性个体的外周血单核细胞对复合期多表位肽反应良好。使用缺乏内源性鼠Ⅱ类基因的HIA—DR3转基因小鼠模型,在体内分析了复合期多表位肽的免疫原性和保护效力。用CpG做佐剂的复合期多表位肽免疫动物产生了高水平的IgG以及多功能CD4’T细胞,它们能够产生HLA-DR3限制性表位特异性的IFN-y、TNF和IL-2。重要的是,当作为预防性疫苗时用结核菌攻击之后,复合期多表位肽的免疫降低了肺部结核杆菌的数量。考虑到可用于免疫识别的潜在Mtb抗原的广谱性,我们的模型数据证明了复合期多表位肽疫苗预防结核病的潜力。     

034 抗原特异性T细胞计数法快速检测结核分枝杆菌感染

迄今为止对于检测潜在的结核分枝杆菌(简称结核杆菌)感染尚无可靠的方法,即使在活动性结核病人中,感染也是经常未被证实。作者设想,结核杆菌抗原特异性T细胞数可能表明感染,故计数了4……     

结核分枝杆菌与树突状细胞相互作用的研究进展

结核分枝杆菌(Mycobacterium tuberculosis, MTB)感染引起的结核病是严重威胁人类健康的慢性传染病。树突状细胞(dendritic cell, DC)是重要的抗原提呈细胞及连接机体固有免疫和适应性免疫应答的桥梁细胞。DC通过表面表达受体识别并吞噬病原体,参与抗原提呈,并发育成熟,同时分泌不同类型的细胞因子,决定T细胞分化方向,最终影响细胞免疫应答效应。在MTB感染过程中各成分与DC相互作用的特性研究,是分析MTB毒力基因及致病机理的基础,并可为结核疫苗研究提供候选优势抗原。现对目前MTB与DC的相互作用机制的研究进展作一概述。     

DNA疫苗初免-BCG加强免疫法提高小鼠抗结核分枝杆菌感染效率的研究

对结核分枝杆菌DNA四价疫苗(编码Ag85B,MPT64,MPT70和TB10.4抗原)初发免疫、卡介苗(BCG)加强免疫后小鼠产生免疫应答的能力和抗结核杆菌感染效率进行了分析.攻毒后细菌计数结果显示,DNA初免、BCG加强组肺脏和脾脏载菌数的对数值比阴性对照组下降1.0～1.3(P<0.01),且显著低于DNA四价苗和BCG组(P<0.05).3次免疫后,BCG加强组外周血中CD4 和CD8 T淋巴细胞显著增多(P<0.05);经4种抗原分别刺激,BCG加强组脾细胞产生的抗原特异性IFN-γ和IL-2水平显著高于其他免疫组,其中Ag85B抗原诱导产生的IFN-γ浓度为1250ng/L,IL-2浓度为230ng/L,分别是DNA四价苗组的1.6,1.7倍(P<0.05),是BCG组PPD诱导产生相应细胞因子浓度的2.6倍和2.2倍(P<0.05);此外,BCG加强组肺脏中分泌穿孔素的淋巴细胞数量也显著增加(P<0.05).结果表明,DNA初发免疫、BCG加强免疫法能显著提高小鼠CD4 ,CD8 T细胞介导的免疫应答,增强小鼠抗结核杆菌感染能力,是提高结核病疫苗免疫效果的新途径.     

抗结核分枝杆菌疫苗的研究进展

结核病是由结核分枝杆菌感染引起的传染病,细胞免疫中的CD_4^+T细胞、CD_8^+T细胞、Th17细胞在对抗结核分枝杆菌感染中发挥重要作用,新近研究显示抗体特定的糖链修饰有助于清除病原体,提示体液免疫也可能参与免疫保护。目前使用的疫苗——卡介苗对婴幼儿重症结核病具有良好的保护力,但是对成人肺结核保护力欠佳,所以需要研发新的疫苗。目前已有数个新型疫苗进入临床试验。本文就结核分枝杆菌的免疫保护机制作一简要介绍,主要阐述现用疫苗——卡介苗及新型疫苗的研究现状,让读者对上述知识的进展有所了解。     

IRF4与BATF在LCMV刺激下对CD8~+ T细胞功能有重要影响

<正>丙型肝炎、艾滋病等慢性病毒感染是威胁人类健康的主要疾病之一。由效应CD8+T细胞介导的细胞免疫功能在清除被感染细胞过程中至关重要,而过度的免疫应答也可造成正常组织细胞损伤,二者的平衡受CD8+T细胞功能决定。然而,目前CD8+T细胞功能调控因子及机制尚不清楚。干扰素调节因子4(interferon regulatory factor 4,IRF4)是B细胞成熟及CD4+T细胞亚群维持、分化的关键因子,然而其对     

结核分枝杆菌的免疫学研究进展

由结核分枝杆菌引起的结核病多年来依然是世界范围内严重的公共卫生问题。结核杆菌的致病特点是可在体内巨噬细胞中长期存活,形成潜伏感染。本文就结核杆菌感染过程中机体的免疫应答过程,尤其是潜伏感染形成机制等方面进行了综述,以期为结核病新型疫苗的研发提供参考。     

结核病疫苗研究进展

随着对抗结核免疫机制的深入研究,新型结核疫苗的研发也更加理性和成熟。近期研究表明,CD4 T细胞多功能至关重要,人类CD8和γδT细胞也有抗结核免疫保护作用,是新型疫苗设计有潜力的T细胞靶点。系统的"组学"技术大规模筛选有可能发现更多强免疫原性的抗原。不同表达时期的多抗原组成的多价疫苗对不同感染时期的结核都有预防作用。针对潜伏感染或已经感染个体配合化学药物使用的新型治疗性疫苗,有望促进清除残留的结核分枝杆菌。     

结核病免疫机制及疫苗研究进展

结核病是一种棘手的重大传染病.虽然存在一些有一定疗效的治疗药物,亦有预防性疫苗--卡介苗(BCG);但结核病仍在世界范围流行,且发病率和病死率居高不下.结核病的免疫病理机制及疫苗研究近年来取得了一定的进展.结核分枝杆菌通过Toll样受体(TLR)等模式识别受体,激活巨噬细胞的天然免疫反应,清除细菌和调节获得性免疫反应....     

In vivo depletion of CD11c+ cells delays the CD4+ T cell response to Mycobacterium tuberculosis and exacerbates the outcome of infection

Although dendritic cells (DC) are potent APC that prime T cells against many pathogens, there is no direct evidence that DC are required for immunity to Mycobacterium tuberculosis (Mtb) infection. The requirement for DC to prime the CD4+ T cell response following Mtb infection was investigated using pCD11c-diptheria toxin receptor/GFP transgenic mice, in which DC can be transiently ablated in vivo. We show a critical role for DC in initiation of the CD4+ T cell response to the mycobacterial Ag early secretory Ag of tuberculosis 6. The delay in initiating the Ag-specific T cell response led to impaired control of Mtb replication. Interestingly, DC were not required for the secondary CD4+ T cell response following Mtb infection in peptide-vaccinated mice. Thus, this study shows that DC are essential for the initiation of the adaptive T cell response to the human pathogen Mtb.     

CD4^＋CD25^＋调节性T细胞与人类获得性免疫缺陷病毒感染

CD4^＋CD25^＋是调节性T细胞中功能最重要的一类。它是一类具有特殊免疫调节功能的T细胞亚群。它能够抑制自身免疫病的发生和发展,参与肿瘤免疫的调节,同时在感染和移植免疫中也发挥着极其重要的作用。T细胞的这一亚群具有免疫调节和免疫抑制的特性,新近发现它亦与爱滋病的发生、发展关系密切。HIV进入人体后,CD4^＋CD25^＋调节性T细胞抑制了机体的免疫效应但它也同时被感染,最终由于细胞毒的作用而死亡。由于调节性T细胞数量的减少不能有效的发挥其抑制作用,HIV持续的过度活化使得T细胞逐渐耗竭说明在HIV发生、发展的不同阶段Treg细胞可能都发挥了免疫抑制作用,但是却对HIV感染与爱滋病发病的进程产生了不同的效应。此外,CD4^＋CD25^＋调节性T细胞还与HIV病毒的持续存在密切相关。本文就CD4^＋CD25^＋调节性T细胞与人类获得性免疫缺陷病毒（HIV）感染之间关系进行初步的探讨。     

IL-23 and IL-17 in tuberculosis

Tuberculosis is a chronic disease requiring the constant expression of cellular immunity to limit bacterial growth. The constant expression of immunity also results in chronic inflammation, which requires regulation. While IFN-gamma-producing CD4+ T helper cells (Th1) are required for control of bacterial growth they also initiate and maintain a mononuclear inflammatory response. Other T cell subsets are induced by Mycobacterium tuberculosis (Mtb) infection including those able to produce IL-17 (Th17). IL-17 is a potent inflammatory cytokine capable of inducing chemokine expression and recruitment of cells to parenchymal tissue. Both the IL-17 and the Th17 response to Mtb are largely dependent upon IL-23. Although both Th17 and Th1 cells are induced following primary infection with Mtb, the protective response is significantly altered in the absence of Th1 cells but not in the absence of Th17. In contrast, in vaccinated animals the absence of memory Th17 cells results in loss of both the accelerated memory Th1 response and protection. Th1 and Th17 responses cross-regulate each other during mycobacterial infection and this may be important for immunopathologic consequences not only in tuberculosis but also other mycobacterial infections.     

BCG induces protection against Mycobacterium tuberculosis infection in the Wistar rat model

Our understanding of the correlation of Mycobacterium bovis Bacille Calmette-Guerin (BCG)-mediated immune responses and protection against Mycobacterium tuberculosis (Mtb) infection is still limited. We have recently characterized a Wistar rat model of experimental tuberculosis (TB). In the present study, we evaluated the efficacy of BCG vaccination in this model. Upon Mtb challenge, BCG vaccinated rats controlled growth of the bacilli earlier than unvaccinated rats. Histopathology analysis of infected lungs demonstrated a reduced number of granulomatous lesions and lower parenchymal inflammation in vaccinated animals. Vaccine-mediated protection correlated with the rapid accumulation of antigen specific CD4(+) and CD8(+) T cells in the infected lungs. Immunohistochemistry further revealed higher number of CD8(+) cells in the pulmonary granulomas of vaccinated animals. Evaluation of pulmonary immune responses in vaccinated and Mtb infected rats by real time PCR at day 15 post-challenge showed reduced expression of genes responsible for negative regulation of Th1 immune responses. Thus, early protection observed in BCG vaccinated rats correlated with a similarly timed shift of immunity towards the Th1 type response. Our data support the importance of (i) the Th1-Th2 balance in the control of mycobacterial infection and (ii) the value of the Wistar rats in understanding the biology of TB.     

结核免疫应答相关白细胞介素的作用机制研究进展

白细胞介素(简称白介素)能够调控免疫细胞的分化、增殖及效应功能。结核抗原特异性诱导的白介素的表达水平能够表征结核杆菌感染后的机体状态。在机体的抗结核免疫应答中,白介素可以直接调控吞噬细胞对胞内感染结核杆菌的杀菌活性;也能够调控效应性T细胞的增殖,并进一步激活吞噬细胞的杀菌功能。目前,部分白介素已被证明有望用于结核病的免疫辅助治疗,正在进行相关临床实验。本文对白介素调控免疫细胞抗结核免疫应答的研究进展进行综述,以期为制定结核病的白介素免疫辅助治疗方案提供指导。     

Distinct effector memory CD4+ T cell signatures in latent Mycobacterium tuberculosis infection, BCG vaccination and clinically resolved tuberculosis

Two billion people worldwide are estimated to be latently infected with Mycobacterium tuberculosis (Mtb) and are at risk for developing active tuberculosis since Mtb can reactivate to cause TB disease in immune-compromised hosts. Individuals with latent Mtb infection (LTBI) and BCG-vaccinated individuals who are uninfected with Mtb, harbor antigen-specific memory CD4(+) T cells. However, the differences between long-lived memory CD4(+) T cells induced by latent Mtb infection (LTBI) versus BCG vaccination are unclear. In this study, we characterized the immune phenotype and functionality of antigen-specific memory CD4(+) T cells in healthy BCG-vaccinated individuals who were either infected (LTBI) or uninfected (BCG) with Mtb. Individuals were classified into LTBI and BCG groups based on IFN-γ ELISPOT using cell wall antigens and ESAT-6/CFP-10 peptides. We show that LTBI individuals harbored high frequencies of late-stage differentiated (CD45RA(-)CD27(-)) antigen-specific effector memory CD4(+) T cells that expressed PD-1. In contrast, BCG individuals had primarily early-stage (CD45RA(-)CD27(+)) cells with low PD-1 expression. CD27(+) and CD27(-) as well as PD-1(+) and PD-1(-) antigen-specific subsets were polyfunctional, suggesting that loss of CD27 expression and up-regulation of PD-1 did not compromise their capacity to produce IFN-γ, TNF-α and IL-2. PD-1 was preferentially expressed on CD27(-) antigen-specific CD4(+) T cells, indicating that PD-1 is associated with the stage of differentiation. Using statistical models, we determined that CD27 and PD-1 predicted LTBI versus BCG status in healthy individuals and distinguished LTBI individuals from those who had clinically resolved Mtb infection after anti-tuberculosis treatment. This study shows that CD4(+) memory responses induced by latent Mtb infection, BCG vaccination and clinically resolved Mtb infection are immunologically distinct. Our data suggest that differentiation into CD27(-)PD-1(+) subsets in LTBI is driven by Mtb antigenic stimulation in vivo and that CD27 and PD-1 have the potential to improve our ability to evaluate true LTBI status.     

A gamma interferon independent mechanism of CD4 T cell mediated control of M. tuberculosis infection in vivo

CD4 T cell deficiency or defective IFNγ signaling render humans and mice highly susceptible to Mycobacterium tuberculosis (Mtb) infection. The prevailing model is that Th1 CD4 T cells produce IFNγ to activate bactericidal effector mechanisms of infected macrophages. Here we test this model by directly interrogating the effector functions of Th1 CD4 T cells required to control Mtb in vivo. While Th1 CD4 T cells specific for the Mtb antigen ESAT-6 restrict in vivo Mtb growth, this inhibition is independent of IFNγ or TNF and does not require the perforin or FAS effector pathways. Adoptive transfer of Th17 CD4 T cells specific for ESAT-6 partially inhibited Mtb growth while Th2 CD4 T cells were largely ineffective. These results imply a previously unrecognized IFNγ/TNF independent pathway that efficiently controls Mtb and suggest that optimization of this alternative effector function may provide new therapeutic avenues to combat Mtb through vaccination.