Neuropilin-2 in Alloimmunity

同种免疫中的 Neuropilin-2

• 批准号: 10577824
• 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/10577824
• 关键词: Acute; Address; Allografting; Antigens; Area; Binding; Biological; Biological Process; Biology; Boston; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cell physiology; Cell surface; Cells; Cellular Metabolic Process; Chronic; Collaborations; Development; Eragrostis; FOXP3 gene; FRAP1 gene; Family; Future; Graft Rejection; Graft Survival; Growth; Homeostasis; Human; Immune; Immune response; Immunity; Immunosuppression; In Vitro; Individual; Knock-out; Knockout Mice; Life; Ligands; Link; Literature; Malignant Neoplasms; Mediating; Mediator; Membrane Glycoproteins; Metabolic Pathway; Minor; Modeling; Molecular; Mus; Neuropilin-1; Neuropilin-2; Neuropilins; Organ Transplantation; Outcome; PIK3CG gene; Pathway interactions; Pediatric Hospitals; Prevention; Process; Proliferating; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Proposals; Resolution; Role; SEMA3F gene; Semaphorins; Shapes; Signal Induction; Signal Transduction; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Transplantation; allograft rejection; angiogenesis; axon guidance; cell growth; cell type; clinically relevant; effector T cell; end-stage organ failure; heart allograft; immune function; immunoregulation; in vivo; inhibitor; innovation; insight; interest; isoimmunity; migration; novel; pharmacologic; plexin; post-transplant; prevent; receptor; response; restraint; 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.

项目摘要/摘要 同种异体移植排斥的特征是效应子CD4+ T细胞激活供体抗原和A 对移植物的强烈细胞和体液攻击。但是，CD4+ T细胞中的多个细胞内信号 共同运行以控制和调节效应子同种异体，并提议此过程 免疫调节是反应的重要组成部分。 Neuropilin（NRP） 受体NRP-1和NRP-2是单个跨膜糖蛋白，最初是 被发现为轴突引导的化学螺栓介质。但是，他们现在被认为功能 在广泛的重要生物学过程中，包括迁移，血管生成和细胞生长。在 此外，最近已显示它们在免疫反应中具有多能功能 肿瘤的启动和进展。在过去的十年中，几个小组确定了关键功能 NRP-1的免疫力，特别与其在诱导的Tregulatory细胞上的表达有关，在该细胞中起作用 增强免疫调节。相比之下，关于NRP-2的免疫功能知之甚少 直到最近才证明它是在免疫细胞上表达的。在初步研究中，我们发现 NRP-2在人和鼠CD4+效应子和调节细胞的子集上表达。 此外，我们发现Semaphorin3F是NRP-2的良好配体，有效抑制PI-3K 据报道调节CD4+ T细胞激活的活性以及MTOR信号传导。另外，我们发现 NRP-2基因敲除小鼠的CD4+ T细胞在体外激活后增强效应子响应 和体内。这些观察结果已塑造了一个工作模型，该模型诱导了NRP-2的表达 关于CD4+ T细胞的作用以调节激活，它们表明其生物学作用具有 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+子集中的调节信号反应和细胞代谢，2） Semaphorin3F是否用于调节CD4+ T细胞激活反应，3）是否评估是否是否 可以在体内利用SEMA3F-NRP-2相互作用，以增加移植后免疫调节 和/或诱导限制癌症生长的Teffector反应。我们将测试CD4+ T细胞的假设 NRP-2与Semaphorin3F和/或其他配体相互作用，以调节Teffector细胞激活和TO 移植后增强TREGULATION细胞功能和免疫调节。我们提出了两个特定的 我们将要：1）确定NRP-2诱导的调节信号的机制和 CD4+ T细胞子集中NRP-2损失的后果，2）确定CD4+ T细胞NRP-2在中的功能 预防排斥和长期同种移植生存。总的来说，这些创新研究将有 具有巨大意义和相关性的广泛科学和生物学意义。