抑制性受体对淋巴细胞活化的调节作用

淋巴细胞在接受正向活化信号的同时也接受各种抑制性信号的调节,以维持机体正常的稳态,避免免疫应答过度对机体的病理损坏。调节淋巴细胞活化的抑制性受体主要包括3类:识别MHC分子的抑制性受体、抑制性Fc受体及与B7家族成员结合的抑制性受体,系统地了解其种类、配体、作用机制、与疾病的关系等将为人们进一步深入了解免疫应答的调控机制提供参考。     

B/T细胞弱化分子-CD28超家族一个新的共抑制分子的研究进展

B／T细胞弱化分子（BTLA）是最近发现的CD28家族共抑制分子，主要表达于B细胞、T细胞和抗原递呈细胞表面。BTLA的配体是TNF超家族成员疱疹病毒进入介质（HVEM）。HVEM-BTLA信号途径对T、B细胞的活化起负调节作用，在调节机体免疫应答，维持自身免疫稳定中起着十分重要的作用。深入研究BTLA的生物学功能及其作用机制对探寻治疗肿瘤、自身免疫性疾病、移植排斥反应、变态反应性疾病等的新干预措施具有重要意义。     

LIGHT-HVEM—BTLA共信号分子的研究进展

BTLA是新近发现的一个CD28超家族共抑制分子,它的配体不是B7家族成员而是TNF受体超家族成员HVEM。HVEM同时还存在一个TNF超家族的配体,即T细胞上可诱导表达的与HSV的糖蛋白D竞争结合HVEM的淋巴毒素类似物（LIGHT）。HVEM可以作为一个分子开关,通过结合LIGHT或BTLA7E免疫调节中发挥不同的作用。     

BTLA信号通路在免疫调节中的作用

BTLA(CD272)属于免疫球蛋白超家族成员,广泛表达于免疫细胞,其配体为HVEM。BTLA基因敲除小鼠淋巴器官发育基本正常,但TCR诱导的免疫应答反应显著增强,CD8记忆T细胞数量显著增多;抗原特异性IgG反应增强,并逐步出现自身抗体、高丙球蛋白血症以及自身免疫性肝炎样疾病。这些结果证明,BTLA具有抑制细胞及体液免疫反应的功能。BTLA信号通路与部分自身免疫性疾病、艾滋病等感染性疾病、肿瘤和移植物抗宿主病等的发生和发展密切相关,调控BTLA信号通路有望用于相关疾病的免疫治疗。     

新型负性共刺激分子-BTLA的研究进展

BTLA(B and T lymphocyte attenuator)是近年发现的免疫球蛋白表面分子家族成员,其与细胞毒T淋巴细胞抗原-4(CTLA-4)、程序坏死因子-1(PD-1)构成了一组抑制性受体,主要在T、B淋巴细胞上表达.BTLA4与其配体结合后,对活化的T细胞可产生抑制效应,从而防止过强的细胞免疫应答,维持耐受,保护机体免受自身免疫反应的损伤.目前对于BTLA的配体,以及BTLA与配体相互作用的确切机制尚未完全明确,故就近年来关于BTLA的分子结构,表达与分布情况,配体分子,及其在免疫应答中作用的研究进展作一综述.     

自身免疫疾病中的LIGHT-LTβR/HVEM信号通路的研究进展

LIGHT( TNFSF14)的两个主要受体:HVEM和LTβR,均为TNFR超家族成员.LIGHT-HVEM途径是重要的T细胞共刺激信号途径,而LIGHT-LTβR在改变树突细胞和间质细胞的功能方面发挥重要作用.HVEM还可与两个免疫球蛋白超基因家族成员即抑制T细胞活化的BTLA和CD160相互作用,HVEM在刺激和抑制信号之间充当一种分子开关.人和实验动物模型研究显示LIGHT-LTβR/HVEM途径在自身免疫疾病的炎症反应和病理发生中起重要的免疫调节作用.因此,在免疫相关疾病的免疫干预治疗中,LIGHT是一种良好的潜在靶标.本文就LIGHT-LTβR/HVEM途径在免疫相关疾病中作用的最新研究进展做一综述.     

固有免疫模式受体NALPs的信号通路及其与自身免疫性疾病的研究进展

随着对固有免疫模式受体(NALPs)家族蛋白研究的深入,人们了解到NALPs家族蛋白与Toll样受体一样广泛参与对病原体的识别及免疫应答.免疫性疾病与NALPs家族蛋白尤其是NALP1和NALP3相关.本文主要介绍了NALPs家族蛋白的结构、分布、识别配体及信号通路,探讨了NALP1和NALP3在免疫炎症反应中的机制及其与免疫性疾病中的作用.     

人共信号分子HVEM在外周血PBMC表达特性及其对T细胞的生物学作用

HVEM既可作为受体与LIGHT作用传递正性共刺激信号,又能作为配体作用于BTLA介导负性共抑制信号。为深入探讨HVEM对T细胞复杂而又独特的调控作用,本文研究了HVEM在免疫细胞上的表达特性,初步探讨了T细胞表达的HVEM分子所介导的生物学作用。采用LPS刺激人新鲜PBMC,以及PHA或PMA/IM刺激活化T细胞;间接免疫荧光标记和流式细胞术检测HVEM表达;MTT法分析T细胞增殖作用。结果显示,HVEM在不同条件刺激活化的T细胞表面均呈现先上调后下调表达;T细胞增殖试验表明,基因转染细胞L929/LIGHT能够明显促进T细胞的增殖及IL-2和IFN-γ的分泌,而以抗人BTLA单抗在一定程度上模拟HVEM所介导的BTLA/HVEM信号能够明显抑制T细胞增殖作用及细胞因子IL-2、IFN-γ和IL-10的产生。     

Toll样受体在机体抗病毒免疫反应中的作用

哺乳动物的Toll样受体(TLR)家族具有模式识别受体的功能,其可以识别微生物的保守分子成分,启动机体的固有免疫系统,从而帮助机体清除病原体.利用TLR敲除的动物或细胞模型进行的研究使人们认识到TLR在机体抗病毒免疫反应中发挥着重要作用.病毒与宿主细胞的TLR结合后,通过NF-κB或IRF-3的信号路径激活细胞因子的表达,从而激发免疫应答.研究TLR如何与病原体结合及如何激活下游基因对深入认识病原体所致相关疾病的发病机制、免疫应答及病理生理具有重要的意义,并为病毒性疾病的临床治疗或免疫预防提供新的思路.     

肿瘤坏死因子受体超家族成员HVEM/TR2研究进展

HVEM/TR2是近来发现的肿瘤坏死因子受体超家族成员,可与单纯疱疹病毒包膜糖蛋白D(HSV-gD)结合介导HSV感染细胞过程;可与其配体LIGHT结合刺激T细胞增殖,在肿瘤免疫、移植免疫、炎症反应、自身免疫性疾病的发生及胸腺阴性选择等过程中发挥重要的生物学作用。另外,新近发现它可与另一配体BTLA结合而抑制T细胞增殖,可能为自身免疫病的治疗提供新思路。     

B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator

B and T lymphocyte attenuator (BTLA) provides an inhibitory signal to B and T cells. Previously, indirect observations suggested that B7x was a ligand for BTLA. Here we show that BTLA does not bind B7x; instead, we identify herpesvirus entry mediator (HVEM) as the unique BTLA ligand. BTLA bound the most membrane-distal cysteine-rich domain of HVEM, distinct from regions where the ligands LIGHT and lymphotoxin-alpha bound HVEM. HVEM induced BTLA tyrosine phosphorylation and association of the tyrosine phosphatase SHP-2 and repressed antigen-driven T cell proliferation, providing an example of reverse signaling to a non-tumor necrosis factor family ligand. The conservation of the BTLA-HVEM interaction between mouse and human suggests that this system is an important pathway regulating lymphocyte activation and/or homeostasis in the immune response.     

Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways

Summary: Cytokines mediate key communication pathways essential for regulation of immune responses. Full activation of antigen-responding lymphocytes requires cooperating signals from the tumor necrosis factor (TNF)-related cytokines and their specific receptors. LIGHT, a lymphotoxin-β (LTβ)-related TNF family member, modulates T-cell activation through two receptors, the herpesvirus entry mediator (HVEM) and indirectly through the LT-β receptor. An unexpected finding revealed a non-canonical binding site on HVEM for the immunoglobulin superfamily member, B and T lymphocyte attenuator (BTLA), and an inhibitory signaling protein suppressing T-cell activation. Thus, HVEM can act as a molecular switch between proinflammatory and inhibitory signaling. The non-canonical HVEM–BTLA pathway also acts to counter LTβR signaling that promotes the proliferation of antigen-presenting dendritic cells (DCs) within lymphoid tissue microenvironments. These results indicate LTβ receptor and HVEM–BTLA pathways form an integrated signaling circuit. Targeting these cytokine pathways with specific antagonists (antibody or decoy receptor) can alter lymphocyte differentiation and activation. Alternately, agonists directed at their cell surface receptors can restore homeostasis and potentially reset immune and inflammatory processes, which may be useful in treating autoimmune and infectious diseases and cancer.     

TNF Superfamily Networks: bidirectional and interference pathways of the herpesvirus entry mediator (TNFSF14)

The herpesvirus entry mediator (HVEM; TNFRSF14) can activate either proinflammatory or inhibitory signaling pathways. HVEM engages two distinct types of ligands, the canonical TNF-related cytokines, LIGHT and Lymphotoxin-α, and the Ig-related membrane proteins, BTLA (B and T lymphocyte attenuator) and CD160. Recent evidence indicates that the signal generated by HVEM depends on the context of its ligands expressed in trans or in cis. HVEM engagement by all of its ligands in trans initiates bidirectional signaling. In contrast, na?ve T cells coexpress BTLA and HVEM forming a cis-complex that interferes with the activation of HVEM by extraneous ligands in the surrounding microenvironment. The HVEM Network is emerging as a key survival system for effector and memory T cells in mucosal tissues.     

The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation

The tumor necrosis factor (TNF) receptor superfamily member herpesvirus entry mediator (HVEM) (TNFRSF14) regulates T-cell immune responses by activating both inflammatory and inhibitory signaling pathways. HVEM acts as both a receptor for the canonical TNF-related ligands, LIGHT [lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed on T lymphocytes] and lymphotoxin-α, and as a ligand for the immunoglobulin superfamily proteins BTLA (B and T lymphocyte attenuator) and CD160, a feature distinguishing HVEM from other immune regulatory molecules. The ability of HVEM to interact with multiple ligands in distinct configurations creates a functionally diverse set of intrinsic and bidirectional signaling pathways that control both inflammatory and inhibitory responses. The HVEM system is integrated into the larger LTβR and TNFR network through extensive shared ligand and receptor usage. Experimental mouse models and human diseases indicate that dysregulation of HVEM network may contribute to autoimmune pathogenesis, making it an attractive target for drug intervention.     

The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation

Summary:  CD160 is a newly identified ligand for HVEM (herpes virus entry mediator). Previously identified HVEM ligands include BTLA (B- and T-lymphocyte attenuator), LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes) and LTα (lymphotoxin-α). The binding of LIGHT or LTα to HVEM delivers a costimulatory signal, whereas the binding of BTLA or CD160 to HVEM delivers a coinhibitory signal. Thus, HVEM is a bidirectional switch regulating T-cell activation in a costimulatory or coinhibitory fashion whose outcome depends on the ligand engaged. The cysteine-rich domain 1 (CRD1) of HVEM is essential for the binding of coinhibitory ligands CD160 and BTLA but not costimulatory ligand LIGHT. Deletion or blockade of HVEM CRD1 abolishes the binding of CD160 and BTLA, but not LIGHT, and converts HVEM to a dominant costimulatory molecule, possibly through the loss of negative signaling by CD160/BTLA. Therapies targeting the CRD1 of HVEM to block BTLA and CD160 binding are being developed to enhance immune responses and vaccination.     

BTLA:一个新发现的CD28超家族共刺激分子

BTLA是新近发现的一个CD8超家族共刺激分子,它与CTLA-4、PD-1有相似的结构和功能,对T细胞活化起负性调控作用,同时还可作为胸腺细胞阳性选择的早期标志。研究发现BTLA可与HVEM直接结合,目前多认为HVEM是BTLA的配体。BTLA—HVEM相互作用沟通了CD28及TNFR两个共刺激分子超家族,是一个比较特别的．CD28超家族分子。     

The expression and anatomical distribution of BTLA and its ligand HVEM in rheumatoid synovium

Co-inhibitory signaling from B and T lymphocyte attenuator (BTLA) can suppress lymphocyte activation and maintain peripheral tolerance. However, the expression and anatomical distribution of BTLA and its ligand, herpesvirus entry mediator (HVEM), in rheumatoid arthritis (RA) synovium have not been reported. In this study, we analyzed the expression of HVEM and BTLA in RA synovium by immunohistochemistry, and our results showed that both factors were observed in all four cases of RA samples. At the cellular level, both HVEM and BTLA were found on the cell membrane and in the cytoplasm. Fluorescence dual staining demonstrated that HVEM was chiefly on CD3⁺ T cells, CD68⁺ macrophages, and to a lesser extent was found on CD31⁺ endothelial cells. Similarly, the expression of BTLA was observed on infiltrated CD3⁺ T cells and CD68⁺ macrophages. The co-expression of HVEM and BTLA with some members of the B7 family in these sections was also analyzed, and the results showed that HVEM antigen was also found on B7-H3⁺ capillaries, while it was absent on B7-H1⁺, B7-DC⁺, B7-H4⁺, and Z39Ig⁺ cells. Interestingly, BTLA was observed on B7-H1⁺, B7-H4⁺, and HVEM⁺ cells in the synovium. The characteristic expression and distribution of BTLA/HVEM in the synovium indicated that their signaling probably affects the pathogenesis of RA, and a clear understanding of their functional roles may further elucidate the pathogenesis of this disease.