TIGIT/CD155在恶性肿瘤中的研究进展

T细胞免疫球蛋白和ITIM结构域蛋白(T-cell immunoreceptor with Ig and ITIM domains, TIGIT)是一种共抑制性受体,在T细胞和NK细胞介导的免疫应答过程中发挥重要作用。在肿瘤免疫监视中,TIGIT的作用与PD-1/PD-L1轴在肿瘤免疫抑制中的作用类似;其通过与配体CD155结合抑制T细胞和NK细胞抗肿瘤反应,导致肿瘤细胞发生免疫逃逸。有研究发现抗TIGIT单克隆抗体可减轻小鼠肿瘤负荷;抗TIGIT抗体和抗PD-1抗体可发挥协同抗肿瘤作用。因此,TIGIT/CD155有望成为肿瘤免疫治疗的新靶点和更精准的筛选PD-1/PD-L1抑制剂受益人群的生物标志物。该文就TIGIT及其配体CD155的分子结构、生物学功能及其在恶性肿瘤中的表达和免疫调控作用作一综述。     

PD-L1分子与疾病免疫调节

PD-LI(曾命名为B7-H1)是迄今发现的B7家族中较新的共刺激分子,与T细胞上的配体(PD-1)结合后可调节T细胞的活化及分化.它通过激活初始T细胞、抑制活化的效应T细胞及调节细胞因子的分泌等而参与多种免疫过程.以PD-L1为靶点的免疫调节与动物器官移植排斥反应、自身免疫性疾病、慢性病毒感染、肿瘤免疫逃逸等疾病的发生、发展密切相关.本文就PD-LI在上述疾病中发生、发展及治疗中的作用做一综述.     

负性共刺激分子阻断抗体用于肿瘤治疗的研究进展北大核心CSCD

在免疫系统中,负性共刺激分子可通过受体-配体的结合而抑制免疫应答,避免免疫造成的组织损伤,在维持自身免疫耐受方面发挥重要作用。负性共刺激分子也参与调节肿瘤的发生发展,细胞毒性T细胞相关抗原4(CTLA-4)和程序性死亡分子1(PD-1)主要表达于活化的T细胞,它们与相应配体结合后可传递抑制性信号,从而抑制机体的抗肿瘤免疫,导致肿瘤免疫逃逸的发生。在肿瘤患者中,利用特异性的抗体阻断这些负性共刺激分子,可消除它们的免疫抑制功能,从而促进机体的抗肿瘤免疫应答,实现对肿瘤生长的有效抑制。现针对负性共刺激分子的阻断抗体在肿瘤治疗中的研究进展进行综述。     

负性共刺激分子阻断抗体用于肿瘤治疗的研究进展

在免疫系统中,负性共刺激分子可通过受体-配体的结合而抑制免疫应答,避免免疫造成的组织损伤,在维持自身免疫耐受方面发挥重要作用。负性共刺激分子也参与调节肿瘤的发生发展,细胞毒性T细胞相关抗原4(CTLA-4)和程序性死亡分子1(PD-1)主要表达于活化的T细胞,它们与相应配体结合后可传递抑制性信号,从而抑制机体的抗肿瘤免疫,导致肿瘤免疫逃逸的发生。在肿瘤患者中,利用特异性的抗体阻断这些负性共刺激分子,可消除它们的免疫抑制功能,从而促进机体的抗肿瘤免疫应答,实现对肿瘤生长的有效抑制。现针对负性共刺激分子的阻断抗体在肿瘤治疗中的研究进展进行综述。     

肿瘤免疫逃逸中TIM-3及其相关配体的机制研究进展

T免疫球蛋白及黏蛋白分子3(T cell immunoglobulin and mucin-domain containing molecule 3,TIM-3)是一种Ⅰ型膜表面分子,高表达于Th1细胞,并产生抑制信号从而导致Th1细胞的凋亡。半乳糖凝集素9(galectin 9,Gal-9)是TIM-3的天然配体,可与Th1细胞上的TIM-3结合从而负调节Th1细胞免疫应答,并能诱导Th1细胞凋亡,在肿瘤免疫逃逸中起着重要作用。此外,TIM-3也在单核-巨噬细胞、NK细胞以及DC等表达,并且在不同细胞上表达时与之结合的配体也不尽相同。TIM-3与高迁移率族蛋白1(high mobility group box 1protein,HMGB1)配体、癌胚抗原相关细胞黏附分子1(carcino-embryonic antigen related cellular adhesion molecule 1,CEACAM1)配体结合,均可导致肿瘤免疫逃逸。故以下就TIM-3与其不同配体之间的信号通路在肿瘤免疫逃逸方面的作用研究进展予以综述。     

DcR3及其配体的研究进展

DcR3/TR6是最近发现的可溶性TNFR超家族成员,在归类上属于第三类,其配体具有多样性。它可竞争性地与FasL、LIGHT及,TL1A结合,在肿瘤免疫、移植免疫、自身免疫及抗感染免疫中都发挥着重要的作用。本文拟就DcR3及其配体的研究进展作一综述。     

转录因子Foxp3在肺癌细胞的表达及其意义

目的研究转录因子Foxp3在肺癌细胞中的表达及其对肿瘤免疫的影响。方法用常规RT-PCR检测Foxp3在肺癌细胞系中的表达,进一步用Western blot验证其蛋白水平的表达;将表达Foxp3的肿瘤细胞及用Foxp3 siRNA沉默后的肿瘤细胞分别与CD4+CD25-T细胞共培养,CFSE评价免疫效应细胞增殖情况。结果 Foxp3在肺癌细胞系中出现表达;肺癌细胞与CD4+T细胞进行共培养,可显著抑制共培养体系中CD4+T细胞增殖;肺癌细胞Foxp3表达沉默后,可显著改善共培养体系中肺癌细胞对CD4+T细胞增殖的抑制作用。结论在肺细胞癌细胞系发现Foxp3的表达,肺癌细胞Foxp3的表达参与对肿瘤特异性T细胞增殖的抑制。     

DcR3及其配体的研究进展

DcR3／TR6是最近发现的可溶性TNFR超家族成员，在归类上属于第三类。其配体具有多样性。它可竞争性地与FasL、LIGHT及TLIA结合，在肿瘤免疫、移植免疫、自身免疫及抗感染免疫中都发挥着重要的作用。本文拟就DcR3及其配体的研究进展作一综述。     

PD-1/PD-L在淋巴瘤中的研究进展

淋巴瘤是一组异质性的淋巴造血系统恶性肿瘤。程序性死亡受体1(programmed death-1,PD-1)及其配体(programmed death-ligand,PD-L)在T细胞介导的免疫应答过程中发挥重要作用。PD-1与PD-L1/PD-L2之间的相互作用可引起细胞凋亡以及T细胞耗竭,进而抑制抗肿瘤免疫应答。近年来研究发现以PD-1/PD-L1为靶点的免疫检查点抑制剂可有效地恢复T细胞功能,为肿瘤的治疗带来希望。该文就PD-1/PD-L在淋巴瘤中的免疫组化研究进展作一综述,以期为淋巴瘤的诊疗提供参考。     

Tim3/HMGB1在肿瘤免疫逃逸中的机制研究进展

T细胞免疫球蛋白黏蛋白分子3(Tim-3)是一种1型膜表面蛋白分子,主要在Th1细胞表达,与天然型配体半乳糖凝集素9(galectin-9)反应参与适应性负性免疫调节。此外,Tim-3也在单核-巨噬细胞、自然杀伤细胞以及树突状细胞(DC)表达,参与免疫调节。Tim-3在肿瘤浸润DC高表达,并可与配体高迁移率族蛋白1(HMGB1)结合,通过阻断Toll样受体3(TLR3)、TLR7、TLR9及细胞质中DNA和RNA相关的免疫反应,来抑制核酸介导的固有免疫反应,导致肿瘤免疫逃逸,减弱DNA预防治疗及化疗的效果。本文就Tim-3在肿瘤浸润DC高表达以及Tim-3与配体HMGB1结合参与肿瘤免疫逃逸方面进行综述。     

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.     

Lymphotoxin and LIGHT signaling pathways and target genes

Summary: Lymphotoxins (LTα and LTβ), LIGHT [homologous to LT, inducible expression, competes with herpes simplex virus (HSV) glycoprotein D for HSV entry mediator (HVEM), a receptor expressed on T lymphocytes], tumor necrosis factor (TNF), and their specific receptors LTβR, HVEM, and TNF receptor 1 (TNFR1) and TNFR2, form the immediate family of the larger TNF superfamily. These cytokines establish a critical communication system required for the development of secondary lymphoid tissues; however, knowledge of the target genes activated by these signaling pathways is limited. Target genes regulated by the LTαβ‐LTβR pathway include the tissue‐organizing chemokines, CXCL13, CCL19, and CCL21, which establish cytokine circuits that regulate LT expression on lymphocytes, leading to organized lymphoid tissue. Infectious disease models have revealed that LTαβ pathways are also important for innate and adaptive immune responses involved in host defense. Here, regulation of interferon‐β by LTβR and TNFR signaling may play a crucial role in certain viral infections. Regulation of autoimmune regulator in the thymus via LTβR implicates LT/LIGHT involvement in central tolerance. Dysregulated expression of LIGHT overrides peripheral tolerance leading to T‐cell‐driven autoimmune disease. Blockade of TNF/LT/LIGHT pathways as an intervention in controlling autoimmune diseases is attractive, but such therapy may have risks. Thus, identifying and understanding the target genes may offer an opportunity to fine‐tune inhibitory interventions.     

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。     

Effects of linker-insertion mutations in herpes simplex virus 1 gD on glycoprotein-induced fusion with cells expressing HVEM or nectin-1

Several cell surface molecules, including HVEM and nectin-1, can serve as entry receptors for herpes simplex virus (HSV) and as receptors for virus-induced or viral glycoprotein-induced cell fusion. The viral ligand for these receptors is the HSV envelope glycoprotein gD. A set of linker-insertion and deletion mutants of HSV type 1 (HSV-1) gD was analyzed for effects of the mutations on binding of gD to HVEM and nectin-1, on viral glycoprotein-induced cell fusion with target cells expressing HVEM or nectin-1 and on complementation of infectivity of a gD-null HSV-1 viral mutant. Insertions after amino acid 151 or 225 or deletion of amino acids 234-244 disrupted (i) binding of the mutant forms of gD to both receptors and (ii) functional interactions (cell fusion and complementation) with both receptors, but were without effect on cell surface expression. Insertions in the N-terminal domain of gD (after amino acid 12, 34 or 43) disrupted binding to HVEM and functional activities with HVEM, as expected from a previously reported X-ray structure of a gD-HVEM complex, but were without effect in the case of nectin-1. These and other results indicate that the mutations disruptive of interactions with both receptors probably affect conformations of contact sites that are different for each receptor.     

BTLA/HVEM抑制信号通路研究进展

BTLA是新近发现的Ig家族的抑制性受体,其唯一配体HVEM,来自TNF受体超家族,可与TNF家族的LIGHT结合提供正向刺激信号.而BTLA与HVEM的相互作用传递抑制信号下调淋巴细胞的免疫应答.这两个来自不同家族的受体间的负向调节作用,改变了对传统抑制性信号通路作用方式的看法.通过介绍目前对其生物学特性、信号传导机制及与相关疾病关系的研究,为进一步深入了解免疫应答的调控机制及寻找治疗自身免疫病、移植排斥、肿瘤等疾病的新方法提供参考.     

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.     

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.     

Comparative usage of herpesvirus entry mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus

The herpesvirus entry mediator A (HVEM/HveA) and nectin-1 (HveC/CD111) are two major receptors for herpes simplex virus (HSV). Although structurally unrelated, both receptors can independently mediate entry of wild-type (wt) HSV-1 and HSV-2 by interacting with the viral envelope glycoprotein D (gD). Laboratory strains with defined mutations in gD (e.g. rid1) do not use HVEM but use nectin-2 (HveB/CD112) for entry. The relative usage of HVEM and nectin-1 during HSV infection in vivo is not known. In the absence of a defined in vivo model, we used in vitro approaches to address this question. First, we screened HSV clinical isolates from various origins for receptor tropism and found that all used both HVEM and nectin-1. Second, we determined the numbers of surface receptors on various susceptible and resistant cell lines as well as on primary fibroblasts derived from an individual with cleft lip/palate ectodermal dysplasia (CLPED1). Although CLPED1 cells can only express a defective form of nectin-1, they allowed entry of wild type and mutant HSV strains by usage of either HVEM or nectin-2. Finally, we compared the ability of HVEM and nectin-1 to mediate entry when expressed at varying cell surface densities. Both receptors showed a direct relationship between the number of receptors and HSV susceptibility. Direct comparison of receptors suggests that nectin-1 is more efficient at promoting entry than HVEM. Overall, our data suggest that both receptors play a role during HSV infection in vivo and that both are highly efficient even at low levels of expression.     

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。