PD-1及其配体PD-L1/PD-L2在寄生虫感染免疫中的作用

程序性死亡-1(programmed death1,PD-1)及其配体PD-L1(ligand1of programmed death-1)/PD-L2(ligand2of programmed death-1)是继CTLA-4/CD28后发现的B7/CD28家族分子,能负调控T细胞的活化和细胞因子的分泌,在寄生虫感染免疫、肿瘤免疫和自身免疫性疾病中有重要的临床应用前景。该文对PD-1的生物学特点及其与配体的作用途径等进行综述。     

PD-1/PD-L1途径在慢性病毒感染中的作用

程序性死亡因子配体-1(PD-L1)分子是B7超家族的重要成员,在单核细胞、树突状细胞及大部分外周组织可以广泛诱导性表达。PD-L1可以和程序性死亡-1(PD-1)及CD80受体结合调节淋巴细胞的功能。PD-1/PD-L1信号在病毒感染后效应T细胞免疫耐受中具有重要作用,并且预示阻断该途径可能是抗病毒感染治疗的方向之一。     

程序性细胞死亡分子-1/程序性死亡配体信号通路在风湿性疾病中的研究进展

程序性细胞死亡分子-1(programmed cel]death-1,PD-1)/程序性死亡配体(programmed death ligand,PD-L)信号通路是近年来公认的存在于T、B细胞活化过程中的一条重要的协同刺激信号通路,包括:表达在活化的T、B细胞表面的PD-1和表达在抗原递呈细胞(APC)表面的PD-L.PD-L分为2种:PD-L1和PD-L2.PD-1、PD-L相互识别,介导的生物学作用主要是抑制T、B细胞的增殖,抑制细胞因子的分泌,促进细胞凋亡.在维持机体自身免疫耐受中具有重要意义,阻断PD-1/PD-L信号通路会诱导或加重风湿性疾病.     

程序性死亡受体1/程序性死亡受体配体1通路在1型糖尿病中的研究进展

T1DM是胰岛β细胞损伤导致的Ins绝对缺乏的自身免疫性疾病。程序性死亡受体1(PD-1)/程序性死亡受体配体1(PD-L1)通路，负性调节T细胞功能维持机体自身免疫稳态，在T1DM发生发展中起重要作用。本文综述PD-1/PDL-1通路在T1DM中的研究进展。     

共刺激分子CD28/CTLA-4-B7与1型糖尿病

CD2 8/细胞毒性T淋巴细胞相关抗原 (CTLA) 4与B7的相互作用是T细胞活化的重要调节因子 ,在自身免疫性疾病的发生、发展中起着不同的作用。其中 ,CD2 8 B7的过度表达是自身免疫性 1型糖尿病发生的重要原因之一 ;而CTLA4可使CD2 8 B7共刺激信号中止 ,是T淋巴细胞活化的负性调节信号。因此 ,运用B7单克隆抗体阻断CD2 8 B7通路或通过加强B7 CTLA 4作用来抑制自身免疫活性T细胞 ,有可能成为治疗该病的新手段。     

PD-1/PD-L1在肿瘤治疗中的进展

免疫治疗因其显著的疗效,已成为肿瘤治疗领域的研究热点.程序性死亡受体1(programmed cell death-1,PD-1)存在两个配体,PD-L1(B7-H1)和PD-L2(B7-DC)可与T细胞表面受体PD-1结合,在免疫应答反应中起重要的负调节作用.由于PD-1与其配体结合可导致T细胞的活化、增殖被抑制,甚至诱导T细胞的凋亡,使肿瘤细胞躲避免疫监视,发生免疫逃逸现象.肿瘤细胞能够持续高表达PD-L1,降低机体免疫应答能力.通过阻断PD-1/PD-L1信号通路,可重新激活衰竭T细胞,增强免疫应答反应,加强对肿瘤的控制.抑制多种免疫位点的疗效明显优于单一的PD-1或PD-L1抗体免疫治疗.本文将从PD-1/PD-L1信号通路出发,陈述其机制,研究进展以及在肿瘤免疫联合治疗现状等方面进行综述.     

PD-1/PD-L 1抗体在非小细胞肺癌治疗中的研究现状

程序性死亡因子1(programmed death-1,PD-1)存在于活化的T细胞和 B细胞表面,是一种重要的免疫共抑制分子。当 PD-1与程序性死亡配体1/2(programmed death-ligand 1/2, PD-L1/2)结合后,可以引起一系列的免疫抑制作用,并使肿瘤逃避免疫破坏。阻断 PD-1/PD-L1通路,则可能减弱其对免疫活性细胞的抑制作用,从而达到增强细胞免疫、杀灭肿瘤细胞的目的。目前大量研究证明PD-1/PD-L1抗体在非小细胞肺癌治疗中有显著的抗肿瘤活性。本文将对其研究现状加以综述。     

接受恩替卡韦治疗的慢性乙型肝炎患者外周血单个核细胞B7-H1表达的动态变化

<正>近年的研究[1]逐渐揭示免疫学因素影响着慢性乙型肝炎(CHB)的临床进展。B7-H1(又称PD-L1,CD274)及其受体PD-1是近年发现在T细胞激活中介导负性共刺激信号的分子,已有众多研究证实其在外周免疫耐受、自身免疫性疾病及慢性感染中发挥着重要作用。有研究发现慢性HBV感染患者T淋巴细胞功能的降低可能与患者树突状细胞(dendritic cells,     

程序性死亡受体1/程序性死亡配体1免疫检测点阻滞剂在实体瘤治疗中的临床研究

近年来程序性死亡受体1/程序性死亡配体1(PD-1/PD-L1)免疫检测点阻滞剂在实体瘤治疗上取得振奋人心的效果。PD-1主要表达于活化的T、B细胞,在限制自身免疫及过度炎症反应方面起重要作用;肿瘤微环境中PD-1/PD-L1的高表达使T细胞活性受到过度抑制,从而发生肿瘤免疫逃逸;PD-L1表达水平可能是预测检测点阻滞剂疗效的标志物。免疫治疗因其持久的反应性及较小毒副作用使部分肿瘤患者获益明显。本文旨在阐述主要的PD-1/PD-L1检测点阻滞剂(单抗)近年来在恶性黑色素瘤、肺癌、尿路上皮癌、肾细胞癌等治疗上研究的现状并在获益人群中筛选出可能具有价值的生物学标志物。     

PD-1/PD-L1信号通路与慢性乙型肝炎

目的：程序性死亡分子-1（programmed death-1,PD-1）是近年来发现的属于B7/CD28家族的重要协同刺激分子,与其配体（programmed death -1 ligand,PD-L）结合后在调节T淋巴细胞的活化、分化及增殖功能方面起着重要作用。在慢性HBV感染不同阶段,PD-1表达水平存在差异,且与肝脏炎症程度、ALT及病毒载量等密切相关。通过不同途径阻断PD-1/PD-L1通路可以使耗竭的T淋巴细胞功能得到改善,提示可能是未来抗病毒治疗的方向之一。     

PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells

Both positive and negative regulatory roles have been suggested for the B7 family member PD-L1(B7-H1). PD-L1 is expressed on antigen-presenting cells (APCs), activated T cells, and a variety of tissues, but the functional significance of PD-L1 on each cell type is not yet clear. To dissect the functions of PD-L1 in vivo, we generated PD-L1-deficient (PD-L1^–/–) mice. CD4⁺ and CD8⁺ T cell responses were markedly enhanced in PD-L1^–/– mice compared with wild-type mice in vitro and in vivo. PD-L1^–/– dendritic cells stimulated greater wild-type CD4⁺ T cell responses than wild-type dendritic cells, and PD-L1^–/– CD4⁺ T cells produced more cytokines than wild-type CD4⁺ T cells in vitro, demonstrating an inhibitory role for PD-L1 on APCs and T cells. In vivo CD8⁺ T cell responses also were significantly enhanced, indicating that PD-L1 has a role in limiting the expansion or survival of CD8⁺ T cells. Studies using the myelin oligodendrocyte model of experimental autoimmune encephalomyelitis showed that PD-L1 on T cells and in host tissues limits responses of self-reactive CD4⁺ T cells in vivo. PD-L1 deficiency converted the 129S4/SvJae strain from a resistant to experimental autoimmune encephalomyelitis-susceptible strain. Transfer of encephalitogenic T cells from wild-type mice into PD-L1^–/– recipients led to exacerbated disease. Disease was even more severe in PD-L1^–/– recipients of PD-L1^–/– T cells. These results demonstrate that PD-L1 on T cells, APCs, and host tissue inhibits naïve and effector T cell responses and plays a critical role in T cell tolerance.PD-L1 (B7-H1) is a ligand for programmed cell death-1 (PD-1) and does not bind to other CD28 family members (1). PD-1 is expressed on activated but not resting CD4⁺ and CD8⁺ T, B, and myeloid cells (2, 3). PD-1^–/– mice develop an autoimmune-like phenotype, which is delayed in onset as compared with CTLA-4^–/– mice (4, 5). This phenotype demonstrates an important negative regulatory role for PD-1 and suggests a role for PD-1 in regulating B and/or T cell tolerance.PD-L1 is expressed on resting and up-regulated on activated B, T, myeloid, and dendritic cells (DCs) (1, 6–9). In contrast to B7–1 and B7–2, PD-L1 also is expressed in nonhematopoietic cells (e.g., microvascular endothelial cells), in nonlymphoid organs (e.g., heart and placenta), and in a variety of tumors (6, 8, 10–12). The expression of PD-L1 within nonlymphoid tissues suggests that PD-L1 may regulate self-reactive T or B cells in peripheral tissues and/or may regulate inflammatory responses in the target organs. However, the roles of PD-L1 on T cells, antigen-presenting cells (APCs), and host tissues are not yet clear. Many potential bidirectional interactions occur between PD-L1 and PD-1 because of the broad expression of PD-L1 and the expression of PD-1 on T cells, B cells, and macrophages. Recent studies using anti-PD-L1 mAbs in vivo have suggested a role for PD-L1 in regulating autoimmune diseases (13, 14). However, these studies could not distinguish the importance of PD-L1 expression on T cells, APCs, and host cells. The function of PD-L1 is also unclear because of conflicting results, with some studies suggesting a stimulatory role and others an inhibitory role (1, 6, 11). To determine the obligatory functions of PD-L1 in vivo, we generated PD-L1-deficient (PD-L1^–/–) mice. Our results indicate that PD-L1 in the T cell, APC, and host tissue plays a critical role in negatively regulating T cell responses.     

Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas

BACKGROUND Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1(PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas(G-NECs) remains unknown.AIM To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant.METHODS We investigated the expression of PD-L1 on tumor cells and PD-1^+, CD8^+, and FOXP3^+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR.RESULTS Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43G-NECs, 21(48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival(OS). The high expression of PD-L1 was correlated with abundant PD-1^+ tumor infiltrating lymphocytes(TILs) instead of CD8^+ TILs and FOXP3^+ regulatory T cells(Tregs).Our analysis also suggested that the infiltration of CD8^+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance(P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without.CONCLUSION Our data demonstrated for the first time that high expression of PD-L1 in GNECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in GNECs.     

Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells

Expression of the PD-1 receptor on T cells has been shown to provide an important inhibitory signal that down-modulates peripheral effector responses in normal tissues and tumors. Furthermore, PD-1 up-regulation on chronically activated T cells can maintain them in a partially reversible inactive state. The function of PD-1 in the very early stages of T-cell response to antigen in vivo has not been fully explored. In this study, we evaluate the role of PD-1 and its 2 B7 family ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), in early fate decisions of CD8 T cells. We show that CD8 T cells specific for influenza hemagglutinin (HA) expressed as a self-antigen become functionally tolerized and express high levels of surface PD-1 by the time of their first cell division. Blockade of PD-1 or B7-H1, but not B7-DC, at the time of self-antigen encounter mitigates tolerance induction and results in CD8 T-cell differentiation into functional cytolytic T lymphocytes (CTLs). These findings demonstrate that, in addition to modulating effector functions in the periphery, B7-H1:PD-1 interactions regulate early T-cell-fate decisions.     

Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3

OBJECTIVE: This study was designed to investigate the roles of programmed death-1 (PD-1) and PD-1 ligands (PD-L) in the development of murine acute myocarditis caused by Coxsackievirus B3. PD-1/PD-L belong to the CD28/B7 superfamily, and the PD-1/PD-L pathway is known to transduce a negative immunoregulatory signal that antagonizes the T-cell receptor-CD28 signal and inhibits T-cell activation. METHODS: We first analyzed the expression of PD-L1/PD-L2 on cardiac myocytes in vivo and in vitro. Second, we examined the effects of in vivo treatment with an anti-PD-1, PD-L1, or PD-L2 monoclonal antibodies on the development of myocardial inflammation in C3H/He mice infected with Coxsackievirus B3. Third, to investigate the effects of anti-PD-1 monoclonal antibody treatment on the activation of the infiltrating cells, we examined the expression of interleukin (IL)-2, interferon (IFN)-gamma, CD40 ligand (CD40L), Fas ligand (FasL), and perforin as activation markers in mouse hearts by a semiquantitative PCR method. RESULTS: PD-L1 was markedly induced on cardiac myocytes with acute myocarditis. In vivo anti-PD-1 or -PD-L1 blocking monoclonal antibody treatment increased the myocardial inflammation whereas anti-PD-1 stimulating monoclonal antibody treatment decreased the myocardial inflammation, and anti-PD-L2 monoclonal antibody treatment had no effect. Anti-PD-1 monoclonal antibody treatment significantly increased the expression of IFN-gamma, FasL, CD40L, perforin, and Coxsackievirus B3 genomes in myocardial tissue. CONCLUSION: Our findings strongly suggest that the PD-1/PD-L1 pathway played a pivotal role in suppressing myocardial inflammation and raise the possibility of immunotherapy by stimulating the PD-1/PD-L1 pathway to prevent myocardial damage in viral myocarditis.     

PD-1／PD—L对免疫调节作用的研究进展

程序性死亡分子1（programmed death-1,PD-1）／PD-1的配体（programmed death ligand,PD—L）属于抑制性共刺激分子,能对免疫反应的产生起负调节作用。PD-1在慢性感染性疾病中的功能缺陷型CD8^＋T细胞上高表达,导致功能性CD8^＋T细胞的功能受损,包括细胞增殖、细胞因子分泌和杀伤能力。在肿瘤、自身免疫性疾病和感染性疾病中,PD-1／PD—L参与免疫反应的调节,抑制抗瘤及抗病毒免疫反应,阻断此通路后可以恢复特异性CD8＋T细胞的部分功能,因此,PD-1／PD—L通路可能与肿瘤细胞免疫逃避和病毒感染疾病慢性化有关。     

Computational design of a synthetic PD-1 agonist

Programmed cell death protein-1 (PD-1) expressed on activated T cells inhibits T cell function and proliferation to prevent an excessive immune response, and disease can result if this delicate balance is shifted in either direction. Tumor cells often take advantage of this pathway by overexpressing the PD-1 ligand PD-L1 to evade destruction by the immune system. Alternatively, if there is a decrease in function of the PD-1 pathway, unchecked activation of the immune system and autoimmunity can result. Using a combination of computation and experiment, we designed a hyperstable 40-residue miniprotein, PD-MP1, that specifically binds murine and human PD-1 at the PD-L1 interface with a K_d of ∼100 nM. The apo crystal structure shows that the binder folds as designed with a backbone RMSD of 1.3 Å to the design model. Trimerization of PD-MP1 resulted in a PD-1 agonist that strongly inhibits murine T cell activation. This small, hyperstable PD-1 binding protein was computationally designed with an all-beta interface, and the trimeric agonist could contribute to treatments for autoimmune and inflammatory diseases.

Proper immune system function involves a dynamic and delicate balance of stimulatory and inhibitory receptors that generate an appropriate response when a foreign antigen is encountered and then return the system to stasis to prevent chronic overactivation that could damage healthy tissue. Programmed cell death protein-1 (PD-1) is an inhibitory receptor expressed on most immune cells (1), including activated T cells and regulatory T cells. Upon engagement with one of its ligands, programmed cell death-1 ligand 1 (PD-L1) (2) or programmed cell death-1 ligand 2 (PD-L2) (3), on the surface of another cell, PD-1 signals to suppress the T cell, leading to decreased production of proinflammatory cytokines, inhibition of effector function, and apoptosis (4). The PD-1/PD-L1 pathway is also important in the development (5) and maintenance (6) of both central and peripheral tolerance, in part via regulatory T cells. Due to its critical role in maintaining a healthy, balanced immune system, alterations in PD-1 function in either direction can lead to disease. Many tumors use this pathway to evade the immune system by overexpressing PD-L1 and/or PD-L2 to deactivate tumor-infiltrating lymphocytes (TILs). On the other hand, a decrease in function of the PD-1 pathway can lead to autoimmune and inflammatory phenotypes. Mice lacking PD-1 develop various autoimmune symptoms, including autoimmune cardiomyopathy (7) and a lupus-like disease (8), depending on the genetic background (9). In humans, mutations that affect the regulation of PD-1 have been associated with systemic lupus erythematosus (10), rheumatoid arthritis (11), and progression of multiple sclerosis (12).Antagonistic antibodies targeting PD-1 and PD-L1, often referred to as checkpoint inhibitors, have revolutionized the treatment of cancer (13). Despite the therapeutic potential of this same pathway in autoimmunity, few agonist PD-1 antibodies have been identified, and no PD-1 agonists have yet been approved for clinical use (14). Several groups have demonstrated that treatment with PD-L1-Fc fusions results in varying levels of lymphocyte suppression and reduction in autoimmune phenotypes (15–17). One agonistic antibody has been described that decreased lung inflammation in a mouse model of allergic asthma (18), highlighting the promise of engaging PD-1 signals.Here, we present a de novo-designed hyperstable miniprotein that specifically binds murine PD-1 on human cells and a trimerized version of the binder that strongly inhibits T cell activation with potential for further development as a synthetic PD-1 agonist for the treatment of autoimmunity.     

Expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases

OBJECTIVES: PD-L1 (also B7-H1) and PD-L2 (also B7-DC) are ligands for programmed death-1 (PD-1), which is a member of the CD28/B7 superfamily of costimulatory molecules and plays an inhibitory role on the periphery. Impaired regulation of this system may cause disruption to self-tolerance leading to autoimmunity; however, the role of these molecules in the liver is unknown. Therefore, we examined the expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases. METHODS: We examined the liver expression of these molecules in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) with no previous medical treatment using immunohistochemical staining and real-time PCR, and compared with chronic hepatitis type C (CHC) as a control. RESULTS: Although PD-1, PD-L1, and PD-L2 were expressed in the liver in AIH, PBC, as well as CHC, the expressions were relatively lower in PBC. In AIH, despite more severe inflammation than in CHC, the expression of these molecules was not greater than in CHC, and when compared with the relative expression of PD-L1, PD-L2 was lower in AIH. PD-L1 and PD-L2 expressions were well correlated with the level of IFN-gamma; however, relatively decreased induction for PD-L1 and PD-L2 by IFN-gamma was observed in AIH or PBC than in CHC. CONCLUSION: Modulation of PD-1/PD-L1 and PD-L2 systems may play a role in the development of autoimmune liver diseases.