Role of T cell Specific Adaptor Protein in Alloimmunity

描述（由申请人提供）：同种异体移植排斥反应是由受体对供体抗原的免疫反应介导的，由CD4+ T细胞发起和协调。一旦T细胞遇到同种异体抗原，它们就会扩增和分化为效应T细胞和/或记忆T细胞。激活还会导致调节T细胞的扩增，这些T细胞具有控制免疫反应的功能，并且有人提出这种免疫调节过程对同种异体移植物的长期存活至关重要。在T细胞内，已经发现了几种适配器蛋白在T细胞受体诱导的信号转导中发挥核心作用，并且发现了几种积极参与信号复合物的形成，从而调节T细胞的激活反应。T细胞特异性适配蛋白（TSAd）是一种含有细胞内适配分子的SH2结构域，最初报道其在T细胞中的表达受到限制。越来越多的证据表明，TSAd在T细胞中的功能是复杂的，它在效应反应和调节反应中都很重要。然而，目前还没有研究解决TSAd在同种异体移植排斥反应和/或同种异体免疫反应中的生物学问题。这项探索性研究计划是基于新的初步观察，我们观察到心脏同种异体移植物的TSAd基因敲除受体在同种异体免疫调节方面存在严重缺陷。我们研究的总体目标是表征TSAd如何介导移植后的免疫调节。具体来说，我们计划使用TSAd敲除小鼠作为同种异体移植物的受体，以确定其在排斥过程中的功能，确定其在同种异体反应性T细胞的产生和功能中的作用，并确定同种异体免疫T调节细胞中TSAd活性的推定靶点。我们的假设是，TSAd活性对同种免疫T调节细胞功能的产生至关重要，并且TSAd在免疫调节中的生物学效应是通过其在T细胞中的表达介导的。我们将在两个特定目标中验证这一假设：1)确定TSAd在同种异体移植排斥反应中的功能，并评估其在体内调节同种异体免疫反应中的作用；2)确定TSAd在同种异体免疫调节中的功能作用是否依赖于其在T细胞中的表达。我们相信这些研究是R21机制的理想选择，因为它们将开启该领域新分子的探索，并且它们具有产生高影响力发现的巨大潜力。了解这种受体在T细胞中的作用和功能也可能在移植中具有重要的临床意义，因为它们可能导致识别将免疫反应从免疫/炎症反应转变为耐受反应的靶标。

DESCRIPTION (provided by applicant): Allograft rejection is mediated by the recipient's immunological response to donor antigen, initiated and coordinated by CD4+ T cells. Once T cells encounter alloantigen, they undergo expansion and differentiation into effectors and/or memory T cells. Activation also results in the expansion of regulatory T cells that function to control the immune response, and it is proposed that this process of immunoregulation is critical for long term allograft survival. Within T cells, several adapter proteins have been found to play central roles in T cell receptor-induced signal transduction, and several have been found to be active participants in the formation of signaling complexes, which modulate the T cell activation response. T-cell-Specific Adaptor Protein (TSAd) is a SH2 domain containing intracellular adaptor molecule that was initially reported to be restricted in its expression to T cells. Increasing evidence suggests that the function of TSAd in T cells is complex, and that it is of importance in both effector as well as well as regulatory responses. However, no study has addressed questions about the biology of TSAd in allograft rejection and/or in the alloimmune response. This exploratory research proposal is based on novel preliminary observations in which we observed that TSAd knockout recipients of cardiac allografts have a profound defect in alloimmune regulation. The overall goal of our research is to characterize how TSAd mediates immunoregulation following transplantation. Specifically, we plan to use TSAd knockout mice as recipients of allografts to determine its function in the rejection process, to identify its role in the generation and function of alloreactive T cells and to identify putative targets of TSAd activity within alloimmune T regulatory cells. Our hypothesis is that TSAd activity is critical for the generation of alloimmune T regulatory cell function, and further, that the biological effect(s) of TSAd in immunoregulation are mediated via its expression within T cells. We will test this hypothesis in two specific aims in which we will: 1), determine the function of TSAd in allograft rejection, and evaluate its role in regulatory alloimmune responses in vivo, and 2), determine if the functional effect of TSAd in alloimmune regulation is dependent on its expression within T cells. We believe that these studies are ideal for the R21 mechanism, as they will initiate the exploration of a new molecule in the field, and they have significant potential to result in high impact findings. Understanding roles and function(s) for this adaptor in T cells is also likely to be of great clinical importance in transplantation, as they may lead to the identification of targets that shift the immune response from one of immunity/inflammation to one of tolerance. PUBLIC HEALTH RELEVANCE: Organ transplantation is a life saving therapy for individuals with end stage organ failure, but all transplants eventually fail due to a process called chronic allograft rejection. Ongoing research is focused on the understanding of basic mechanisms leading to the development of chronic rejection and mechanisms whereby the alloimmune response causes graft injury. In this research proposal, we plan to determine if an adaptor protein, called TSAd functions in alloimmunity and if we can learn how TSAd-dependent signals can be manipulated in order to achieve long term graft survival in the future.