Neuropilin-2 in Alloimmunity

项目摘要/摘要 同种异体移植排斥反应的特征是效应者CD4+T细胞对供者抗原和AFP的反应 对移植物进行强烈的细胞和体液攻击。然而，CD4+T细胞内的多个细胞内信号 协同作用以控制和调节效应器同种免疫，并提出这一过程 免疫调节是这一反应的重要组成部分，或许也是更有力的组成部分。神经匹林(NRP) 受体，NRP-1和NRP-2，是单跨膜糖蛋白，最初是 被发现为轴突引导的化学排斥介质。然而，它们现在被认为可以发挥作用 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……里面 此外，它们最近被证明在免疫反应中以及在 肿瘤的发生和发展。在过去的十年中，几个小组已经确定了 NRP-1在免疫中的作用与其在诱导的T调节细胞上的表达显著相关 加强免疫调节。相反，人们对NRP-2的免疫功能知之甚少。 而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在人类和小鼠的CD4+效应和调节细胞亚群上都有表达。 此外，我们还发现NRP-2的配基Semaphorin3F对PI-3K有很强的抑制作用 据报道，调节CD4+T细胞激活的活性以及mTOR信号。另外，我们发现 NRP-2基因敲除小鼠的CD4+T细胞体外激活后增强的效应反应 在活体内。这些观察形成了一个工作模型，在这个模型中，NRP-2的诱导表达 对CD4+T细胞的功能调节激活，他们认为它的生物学效应 同种异体免疫反应结果的后果。我们在R01中的目标是：1)，确定 NRP-2如何调节CD4+细胞亚群的调节信号反应和细胞代谢，2)，评估 Semaphorin 3F是否起到调节CD4+T细胞激活反应的作用，以及3)，评估 可以利用Sema3F-NRP-2在体内的相互作用来增强移植后的免疫调节 和/或诱导抑制肿瘤生长的效应器反应。我们将检验一个假设，即CD4+T细胞 NRP-2与Semaphorin3F和/或其他配体相互作用，调节效应细胞的激活，并 增强移植后T细胞调节功能和免疫调节。我们提出了两个具体的 我们的目标是：1)确定NRP-2诱导的调节信号的机制和 NRP-2在CD4+T细胞亚群中丢失的后果，以及2)，决定了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。总体而言，这些创新研究将具有 在免疫学方面具有重大意义和相关性的广泛科学和生物学意义。

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.