Role of T cell Specific Adaptor Protein in Alloimmunity

描述(申请人提供)：同种异体移植排斥反应是由受者对供者抗原的免疫反应介导的，由CD4+T细胞启动和协调。一旦T细胞遇到同种异体抗原，它们就会经历扩增和分化为效应者和/或记忆性T细胞。激活还会导致调节性T细胞的扩张，这些调节性T细胞具有控制免疫反应的功能，有人认为这一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，已发现几种接头蛋白在T细胞受体诱导的信号转导中发挥核心作用，其中几种蛋白被发现是调节T细胞激活反应的信号复合体形成的积极参与者。T细胞特异性接头蛋白(TSAd)是一种含有SH2结构域的胞内接头分子，最初的报道是限制其在T细胞中的表达。越来越多的证据表明，TSAd在T细胞中的功能是复杂的，它在效应性和调节性反应中都具有重要意义。然而，还没有研究涉及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。这一探索性研究方案是基于新的初步观察，在这些初步观察中，我们观察到同种异体心脏移植的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确定TSAd如何在移植后介导免疫调节。具体地说，我们计划使用TSAd基因敲除小鼠作为同种异体移植的受体，以确定其在排斥反应过程中的功能，确定其在同种异体反应性T细胞的生成和功能中的作用，并确定同种异体免疫T调节细胞中TSAd活性的可能靶点。我们的假设是，TSAd活性对同种异体免疫T细胞调节功能的产生至关重要，而且TSAd在免疫调节中的生物学效应(S)是通过其在T细胞内的表达而介导的。我们将在两个特定的目标中检验这一假说：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效应是否依赖于其在T细胞内的表达。我们认为，这些研究是R21机制的理想选择，因为它们将启动该领域新分子的探索，并具有产生高影响力发现的巨大潜力。了解这个接头在T细胞中的角色和功能(S)在移植中也可能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点。

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.