Neuropilin-2 in Alloimmunity

项目总结/摘要 同种异体移植排斥反应的特征是效应CD 4 + T细胞对供体抗原的应答激活， 细胞和体液对移植物的强烈攻击然而，CD 4 + T细胞内的多种细胞内信号 同时操作以控制和调节效应同种免疫，并且提出了这种免疫过程。 免疫调节是应答的重要且可能更有效的组成部分。神经纤毛蛋白（NRP） 受体NRP-1和NRP-2是单跨膜糖蛋白，它们最初是 被发现是轴突引导的化学排斥介质。然而，现在人们认识到， 在包括迁移、血管生成和细胞生长在内的广泛的重要生物过程中。在 此外，它们最近已被证明在免疫应答中具有多能功能， 肿瘤的发生和发展。在过去的十年里，几个小组已经确定了 NRP-1在免疫中的作用，特别是与其在诱导的T调节细胞上的表达有关， 增强免疫调节。相反，对NRP-2的免疫功能知之甚少 并且直到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CD 4+效应细胞和调节细胞的亚群上表达。 此外，我们发现，脑信号蛋白3F，一个公认的NRP-2的配体，是有效的抑制PI-3 K 活性以及mTOR信号传导，据报道其调节CD 4 + T细胞活化。此外，我们发现， 来自NRP-2敲除小鼠的CD 4 + T细胞在体外活化后产生增强的效应子应答 和体内。这些观察结果形成了一个工作模型，其中NRP-2的诱导表达 对CD 4 + T细胞的作用是调节活化，他们认为其生物学效应具有 同种免疫反应的结果的后果。我们在R 01中的目标是：1）识别 NRP-2如何调节CD 4+亚群中的调节信号应答和细胞代谢，2），评估 Semaphorin 3F是否用于调节CD 4 + T细胞活化应答，以及3）评估Semaphorin 3F是否 Sema 3F-NRP-2相互作用可在体内用于增强移植后的免疫调节 和/或诱导限制癌症生长的T效应子应答。我们将检验CD 4 + T细胞 NRP-2与脑信号蛋白3F和/或另外的配体相互作用以调节T效应细胞活化， 增强T调节细胞功能和移植后的免疫调节。我们提出两个具体的 目的是：1）确定NRP-2诱导的调节信号传导机制， NRP-2在CD 4 + T细胞亚群中损失的后果，和2）确定CD 4 + T细胞NRP-2在CD 4 + T细胞亚群中的功能。 排斥反应的预防和移植物的长期存活。总的来说，这些创新的研究将 广泛的科学和生物学影响，在免疫方面具有重大意义和相关性。

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.