Neuropilin-2 in Alloimmunity

同种免疫中的 Neuropilin-2

• 批准号: 10355442
• 负责人: David M. Briscoe
• 金额: $ 50.9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10355442
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Address; Allografting; Antigens; Area; Binding; Biological; Biological Process; Biological Response Modifier Therapy; Biology; Boston; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cell surface; Cells; Cellular Metabolic Process; Chronic; Collaborations; Development; FOXP3 gene; FRAP1 gene; Family; Future; Glycoproteins; Graft Rejection; Graft Survival; Growth; Homeostasis; Human; Immune; Immune response; Immunity; Immunosuppression; In Vitro; Individual; Knock-out; Knockout Mice; Lead; Life; Ligands; Link; Literature; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic Pathway; Minor; Modeling; Molecular; Mus; Neuropilin-1; Neuropilin-2; Neuropilins; Organ Transplantation; Outcome; Pathway interactions; Pediatric Hospitals; Pharmacology; Prevention; Process; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Proposals; Resolution; Role; SEMA3F gene; Savings; Semaphorins; Signal Transduction; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Transplantation; allograft rejection; angiogenesis; axon guidance; cell growth; cell type; clinically relevant; cohesion; end-stage organ failure; heart allograft; immune function; immunoregulation; in vivo; inhibitor; innovation; insight; interest; isoimmunity; migration; novel; plexin; post-transplant; prevent; receptor; response; selective expression; therapeutic development; tumor initiation; tumor progression

Project Summary/Abstract Allograft rejection is characterized by effector CD4+ T cell activation in response to donor antigen and an intense cellular and humoral attack on the graft. However, multiple intracellular signals within CD4+ T cells operate co-incidentally to control and regulate effector alloimmunity, and it is proposed that this process of immunoregulation is a vital and perhaps more potent component of the response. The neuropilin (NRP) receptors, NRP-1 and NRP-2, are single spanning transmembrane glycoproteins that were initially discovered as chemorepulsive mediators of axonal guidance. However, they are now recognized to function in a wide range of important biological processes including migration, angiogenesis, and cell growth. In addition, they have recently been shown to have pluripotent functions in the immune response as well as in tumor initiation and progression. Over the past decade, several groups have identified critical functions for NRP-1 in immunity, notably related to its expression on induced Tregulatory cells where it functions to augment immunoregulation. In contrast, much less is known about the immunological function of NRP-2 and it has only recently been demonstrated to be expressed on immune cells. In preliminary studies, we find that NRP-2 is expressed on subsets of both human and murine CD4+ effector and regulatory cells. Furthermore, we find that Semaphorin3F, a well established ligand for NRP-2, is potent to inhibit PI-3K activity as well as mTOR signaling that are reported to modulate CD4+ T cell activation. Also, we find that CD4+ T cells from NRP-2 knockout mice mount enhanced effector responses following activation in vitro and in vivo. These observations have shaped a working model whereby the induced expression of NRP-2 on CD4+ T cells functions to modulate activation, and they suggest that its biological effects have consequences for the outcome of the alloimmune response. Our objectives in this R01 are to: 1), identify how NRP-2 modulates regulatory signaling responses and cell metabolism in CD4+ subsets, 2), evaluate whether Semaphorin3F serves to regulate CD4+ T cell activation responses, and 3), evaluate whether Sema3F-NRP-2 interactions can be exploited in vivo to augment immunoregulation post transplantation and/or to induce Teffector responses that limit cancer growth. We will test the hypothesis that CD4+ T cell NRP-2 interacts with Semaphorin3F and/or additional ligands to modulate Teffector cell activation and to augment Tregulatory cell function and immunoregulation following transplantation. We propose two specific aims in which we will: 1), identify the mechanism of NRP-2-induced regulatory signaling and the consequences of NRP-2 loss in CD4+ T cell subsets, and 2), determine the function of CD4+ T cell NRP-2 in the prevention of rejection and in long-term allograft survival. Collectively, these innovative studies will have broad scientific and biological implications of great significance and relevance in immunity.

项目概要/摘要 同种异体移植排斥的特点是效应 CD4+ T 细胞响应供体抗原而激活，并且 对移植物的强烈的细胞和体液攻击。然而，CD4+ T 细胞内存在多种细胞内信号 同时运作以控制和调节效应子同种免疫，并且建议该过程 免疫调节是反应的一个重要组成部分，或许也是更有效的组成部分。神经毡蛋白 (NRP) 受体 NRP-1 和 NRP-2 是单跨膜糖蛋白，最初是 被发现作为轴突引导的化学脉冲介质。然而，它们现在被认为可以发挥作用 广泛的重要生物过程，包括迁移、血管生成和细胞生长。在 此外，最近已证明它们在免疫反应以及免疫反应中具有多能功能。 肿瘤的发生和进展。在过去的十年中，一些团体已经确定了 NRP-1 在免疫中的作用，尤其与其在诱导性调节性细胞上的表达有关，其功能是 增强免疫调节。相比之下，人们对 NRP-2 的免疫功能知之甚少。 最近才被证明在免疫细胞上表达。在初步研究中，我们发现 NRP-2 在人和鼠 CD4+ 效应细胞和调节细胞的亚群上表达。 此外，我们发现 Semaphorin3F（一种成熟的 NRP-2 配体）能够有效抑制 PI-3K 据报道，mTOR 活性以及 mTOR 信号传导可调节 CD4+ T 细胞的激活。另外，我们发现 NRP-2 敲除小鼠的 CD4+ T 细胞在体外激活后增强效应反应 和体内。这些观察结果形成了一个工作模型，通过该模型诱导 NRP-2 的表达 CD4+ T 细胞具有调节激活的功能，他们表明其生物学效应 同种免疫反应结果的后果。我们在此 R01 中的目标是：1)、确定 NRP-2 如何调节 CD4+ 亚群中的调节信号反应和细胞代谢，2)，评估 Semaphorin3F 是否可以调节 CD4+ T 细胞激活反应，以及 3)、评估是否 Sema3F-NRP-2 相互作用可在体内利用来增强移植后的免疫调节 和/或诱导限制癌症生长的 T 效应器反应。我们将检验 CD4+ T 细胞的假设 NRP-2 与 Semaphorin3F 和/或其他配体相互作用，调节 T 效应细胞激活并 增强移植后的调节细胞功能和免疫调节。我们提出两个具体方案 我们的目标是：1)、确定 NRP-2 诱导的调节信号传导机制以及 CD4+ T 细胞亚群中 NRP-2 缺失的后果，以及 2) 确定 CD4+ T 细胞 NRP-2 在 预防排斥反应和同种异体移植物的长期存活。总的来说，这些创新研究将 广泛的科学和生物学意义对免疫具有重要意义和相关性。