活化T细胞核因子与肺动脉高压的研究进展

<正>活化T细胞核因子(nuclear factor of activated T cell,NFAT)是一类具有多向调节功能的转录因子,最初在活化T细胞的核提取物中发现,结合白细胞介素2(interleukin 2,IL-2)启动子,在免疫应答中诱导基因转录,促进T细胞活化[1]。NFAT在哺乳动物组织细胞中广泛表达,在细胞分化、生长过程中起重要作用。越来越多的研究表明,NFAT和肺动脉高压发病机制密切相关。本文主要针对NFAT在肺动脉高压     

钙/钙调神经磷酸酶-活化T细胞核因子信号通路与T细胞活化及支气管哮喘关系的研究进展

钙/钙调神经磷酸酶-活化T细胞核因子信号通路作为T细胞内重要的生物信号转导通路,在T细胞活化中起到调节枢纽的作用,与Th细胞的分化及多种细胞因子的产生有密切关系;而T细胞的浸润和活化在支气管哮喘(简称哮喘)气道慢性炎症及气道重塑的发生、发展过程中具有重要的意义,因此,钙/钙调神经磷酸酶-活化T细胞核因子信号通路可能与哮喘的发生有密切关系,其在哮喘T细胞活化机制中的研究对于揭示哮喘的发病机制和治疗有重要的意义.     

钙／钙调神经磷酸酶-活化T细胞核因子信号通路与T细胞活化及支气管哮喘关系的研究进展

钙／钙调神经磷酸酶-活化T细胞核凼子信号通路作为T细胞内重要的生物信号转导通路,在T细胞活化中起到调节枢纽的作用,与Th细胞的分化及多种细胞闵子的产生有密切关系;而T细胞的浸润和活化在支气管哮喘（简称哮喘）气道慢性炎症及气道重塑的发生、发展过程中具有重要的意义,因此,钙／钙调神经磷酸酶-活化T细胞核因子信号通路可能与哮喘的发生有密切关系,其在哮喘T细胞活化机制中的研究对于揭示哮喘的发病机制和治疗有重要的意义。     

Calcineurin/NFAT信号通路与胰腺β细胞功能

钙调神经磷酸酶／活化T细胞核因子（Calcineurin／NFAT）信号转导通路广泛存在于多种组织器官中。它通过NFAT蛋白的脱磷酸化及核内转位,激活下游基因的转录,调节细胞的生长、发育及功能。最近的研究证明,该通路对胰腺β细胞的生长、发育及内分泌作用过程中相关基因的转录可能也具有刺激作用,揭示了一个有关糖尿病发病机制和治疗的新模式。     

转录因子活化T细胞核因子抑制剂研究进展

活化T细胞核因子(nuclear factor of activated T cells,NFAT)家族分布广泛,生物学功能多样,通过抑制NFAT治疗疾病是目前的研究热点,对NFAT抑制剂的研究取得了丰硕的成果,有些成果已用于临床治疗,如环孢霉素A和他克莫司,随着对NFAT活化及其发挥功能各个环节的研究日渐深入,使多位点、多环节抑制NFAT活性,提高免疫抑制的特异性,减少不良反应成为可能,为研制新型免疫抑制剂带来希望.     

结直肠癌组织中活化T细胞核因子的表达及意义

采用荧光定量逆转录PCR（FQ-RT-PCR）法和免疫组化法检测60例结直肠癌组织及其邻近正常黏膜组织中活化T细胞核因子NFATmRNA及其蛋白,并分析其与结直肠癌临床病理特征的关系。结果结直肠癌组织NFATmRNA的转录水平和NFAT蛋白的表达水平均显著高于邻近正常黏膜组织（P均〈0．05）,二者均与结直肠癌的分化程度、浸润深度、有无淋巴结转移及TNM分期密切相关。结直肠癌组织及邻近正常黏膜组织NFATmRNA转录水平和NFAT蛋白表达水平均呈正相关（r分别为0．240、0．219,P均〈0．05）。认为NFAT在结直肠癌的发生及侵袭转移中发挥重要作用,检测结直肠癌中NFAT表达有助于结直肠癌的恶性程度及生物学行为的判断及预后评估。     

肝细胞癌中细胞因子信号传导抑制因子1与调节性 T淋巴细胞/辅助性T淋巴细胞17平衡的关系

调节性T淋巴细胞(Treg)和辅助性T淋巴细胞17(Th17)在肝细胞癌(HCC)的肿瘤微环境中发挥重要作用,Treg/Th17失衡与HCC的侵袭和进展密切相关。同时,细胞因子信号传导抑制因子1(SOCS1)作为Janus激酶/信号转导和转录激活因子信号通路的负调控因子之一,参与调控Treg细胞和Th17细胞的增殖、分化。本文主要分析HCC中SOCS1与Treg/Th17平衡的关系,探究HCC发生发展过程中的免疫相关机制。     

慢性乙型肝炎发病过程中CD4 T细胞并非单纯“细胞毒”作用

T细胞在慢性乙型肝炎(CHB)的免疫发病机制中的重要作用众所周知。虽然近年的相关研究主要集中在CD8 T细胞耗竭在慢性乙型肝炎发病机制中的作用,但自20世纪80年代开始,很多学者持续关注CD4 T细胞在宿主免疫中发挥的多种关键作用,包括CD4 T细胞促进B细胞成熟并产生抗体、诱导粒细胞趋化、通过CD40/CD40L相互作用参与抗原递呈细胞活化,以及在特定转录因子和细胞因子调控下,分化为功能不同的亚群(包括产生IFNγ/IL-12的Th1细胞,主要产生IL-4的Th2细胞,依赖于转录因子R ORγT产生IL-17/IL-21的Th17细胞和依赖于转录因子FoxP3的T-reg细胞),尤其在参与CD8 T细胞介导的HBV免疫反应中发挥了举足轻重的作用。     

地塞米松调节T细胞免疫应答保护小鼠急性炎性肝损伤的作用

背景:在小鼠急性炎性肝损伤中,地塞米松(Dex)可通过抑制天然免疫细胞功能抑制肝损伤进展,然而T细胞是否参与此保护作用尚少见报道。目的:探讨Dex在急性炎性肝损伤中对T细胞免疫应答的调节效应。方法:6只雄性C57BL/6J小鼠随机分为实验组和模型组,在以脂多糖诱导急性炎性肝损伤模型前1 h,两组分别腹腔注射Dex5 mg/kg和等体积PBS。建模12 h后处死小鼠,行临床评分并检测肝功能;分离脾脏单个核细胞,分析T细胞活化情况以及各T细胞亚群的细胞因子表达、分泌和转录因子表达。结果:实验组小鼠临床评分和血清转氨酶水平均明显低于模型组,脾脏CD44+CD62L-T细胞(活化或记忆性T细胞)比率显著降低,Th1型细胞因子IFN-γ表达、分泌减少,Th2型细胞因子IL-4表达、分泌增加,调节性T细胞(Treg细胞)比率、Th2/Th1、Treg/Th1比值增加;同时,Th1细胞特异性转录因子表达下调,Th2、Treg细胞特异性转录因子表达上调。结论:Dex通过抑制T细胞活化并调节T细胞亚群分化(抑制Th1细胞分化,促进Th2、Treg细胞分化),在急性炎性肝损伤中起一定保护作用。     

调节性T细胞及其与支气管哮喘发病的关系

调节性T细胞（regulatory T cells,Treg）是不同于Th1和Th2的具有调节功能的T细胞亚群,它们可分泌免疫抑制因子IL-10和TGF-β,或通过接触抑制等机制,对效应性T细胞产生强大的抑制作用,在多种免疫性疾病包括哮喘中起重要调节作用。本文就Treg的生物学特点、分化与调控及其与支气管哮喘的关系作一综述,以探讨支气管哮喘发病机制的新思路。     

NFAM1, an immunoreceptor tyrosine-based activation motif-bearing molecule that regulates B cell development and signaling

A functional cDNA cloning system was developed by using a retrovirus library encoding CD8-chimeric proteins and a nuclear factor of activated T cells (NFAT)-GFP reporter cell line to identify molecules inducing NFAT activation. By using this strategy, NFAT activating molecule 1 (NFAM1) was cloned as an immunoreceptor tyrosine-based activation motif (ITAM)-bearing cell surface molecule belonging to the Ig superfamily and is predominantly expressed in spleen B and T cells. NFAM1 crosslinking induced ITAM phosphorylation, ZAP-70/Syk recruitment, NFAT activation, and cytokine production. In vivo overexpression of NFAM1 in bone marrow chimeras and transgenic mice induced severe impairment of early B cell development in an ITAM-dependent manner. In NFAM1-expressing B cells, B cell antigen receptor stimulation induced NFAM1 translocation to lipid raft, and NFAM1 co-crosslinking augmented B cell antigen receptor signaling. The results suggest that NFAM1 modulates B cell signaling through its ITAM, which regulates B cell development.     

Aberrant activation of nuclear factor of activated T cell 2 in lamina propria mononuclear cells in ulcerative colitis

AIM： To investigate the role of nuclear factor of activated T cell 2 （NFAT2）, the major NFAT protein in peripheral T cells, in sustained T cell activation and intractable inflammation in human ulcerative colitis （UC）. METHODS： We used two-dimensional gel-electrophoresis, immunohistochemistry, double immunohistochemical staining, and confocal microscopy to inspect the expression of NFAT2 in 107, 15, 48 and 5 cases of UC, Crohn＇s disease （CD）, non-specific colitis, and 5 healthy individuals, respectively. RESULTS： Up-regulation with profound nucleotranslocation/activation of NFAT2 of lamina propria mononuclear cells （LPMC） of colonic mucosa was found specifically in the affected colonic mucosa from patients with UC, as compared to CD or NC （P〈0.001, Kruskal- Wallis test）. Nucleo-translocation/activation of NFAT2 primarily occurred in CD8＋T, but was less prominent in CD4＋ T cells or CD20＋B cells. It was strongly associated with the disease activity, including endoscopic stage （τ= 0.2145, P=0.0281） and histologic grade （τ= 0.4167, P 〈 0,001）, CONCLUSION： We disclose for the first time the nucleo-translocation/activatin of NFAT2 in lamina propria mononuclear cells in ulcerative colitis. Activation of NFAT2 was specific for ulcerative colitis and highly associated with disease activity. Since activation of NFAT2 is implicated in an auto-regulatory positive feedback loop of sustained T-cell activation and NFAT proteins play key roles in the calcium/calcineurin signaling pathways, our results not only provide new insights into the mechanism for sustained intractable inflammation, but also suggest the calcium-calcineurin/NFAT pathway as a new therapeutic target for ulcerative colitis.     

NFAT control of innate immunity

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway mediates multiple adaptive T-cell functions, but recent studies have shown that calcineurin/NFAT signaling also contributes to innate immunity and regulates the homeostasis of innate cells. Myeloid cells, including granulocytes and dendritic cells, can promote inflammation, regulate adaptive immunity, and are essential mediators of early responses to pathogens. Microbial ligation of pattern-recognition receptors, such as TLR4, CD14, and dectin 1, is now known to induce the activation of calcineurin/NFAT signaling in myeloid cells, a finding that has provided new insights into the molecular pathways that regulate host protection. Inhibitors of calcineurin/NFAT binding, such as cyclosporine A and FK506, are broadly used in organ transplantation and can act as potent immunosuppressive drugs in a variety of different disorders. There is increasing evidence that these agents influence innate responses as well as inhibiting adaptive T-cell functions. This review focuses on the role of calcineurin/NFAT signaling in myeloid cells, which may contribute to the various unexplained effects of immunosuppressive drugs already being used in the clinic.     

T cell signaling: Protein kinase Cθ the immunological synapse and characterization of SLAT a novel T helper 2-specific adapter protein

Triggering of the antigen-specific T cell receptor (TCR) can lead to various functional outcomes, such as activation and proliferation, anergy or cell death. This differential signaling is mainly determined by the quality and quantity of TCR signals, the nature of accessory signals and the differentiation/maturation status of the T cell. In this regard, T cell development and differentiation of the two major T helper (Th) subsets, namely Th1 and Th2 cells, can also be viewed as examples of differential signaling. In the present report, we review two T cell-selective signaling molecules (protein kinase C (PKC) θ and SLAT), which we have studied extensively and that appear to play important roles in the process of differential signaling. The novel PKC isoform PKCθ is selectively expressed in T lymphocytes and is essential for TCR-triggered activation of mature T cells via activation of the nuclear factor-κB and activator protein-1 pathways. Productive engagement of T cells by antigen-presenting cells (APC) results in recruitment of PKCθ to the T cell-APC contact area, the immunological synapse (IS), where it interacts with several signaling molecules to induce activation signals essential for productive T cell activation and interleukin-2 production. These events are associated with PKCθ translocation to membrane lipid rafts, which also localize to the IS. The Vav/Rac pathway promotes the recruitment of PKCθ to the IS or lipid rafts as well as its activation. SLAT is a novel adapter protein, which we isolated recently. It is selectively expressed in Th2 lineage cells, where it is found associated with the TCR-coupled protein tyrosine kinase ZAP-70. Our initial characterization of SLAT indicates that, by regulating the overall strength of TCR signaling, it may play an important role in differential signaling processes, which promote the differentiation and activation of allergy promoting and anti-inflammatory Th2 cells.     

Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice

Although c-Maf is crucial for Th2 differentiation and production of interleukin 4 (IL-4), its regulation is poorly understood. We report that Vav1-/- CD4+ T cells display deficient T-cell receptor (TCR)/CD28-induced IL-4 and c-Maf expression and, conversely, enhanced interferon gamma (IFN-gamma) production and T-bet expression (even when cultured under Th2-polarizing conditions), but intact expression of other Th2 cytokines and GATA-3. Up-regulation of c-Maf was dependent on Ca2+/nuclear factor of activated T cell (NFAT) and, together with IL-4 production, could be rescued in Vav1-/- T cells by Ca2+ ionophore. Deficient IL-4 production was restored by retrovirus-mediated Vav1 expression, but only partially by retroviral c-Maf expression. Similar IL-4 --> IFN-gamma skewing was observed in intact, antigen-primed Vav1-/- mice. Thus, Vav1 is selectively required for IL-4 and c-Maf expression, a requirement reflecting, at least in part, the dependence of c-Maf expression on Ca2+/NFAT signaling.