Role of Novel T Cell Costimulatory Pathways in Allograft Rejection and Tolerance

T细胞免疫球蛋白粘蛋白(TIM)家族是一类新的受体-配体对，在T细胞中发挥重要作用 激活、分化和效应/记忆功能，以及在免疫反应调节中的作用 免疫力和过敏/哮喘。TIM-1由活化的Th1和Th2细胞表达，其表达是 在终末分化的Th2细胞中优先维持。TIM-1的配体是TIM-4，它是 主要表达在APC上。最近的研究表明，TIM-1可能对辅助性T细胞有不同的调节作用 (Th1/Th2)在哮喘/过敏和自身免疫性脑脊髓炎中的分化。目前，人们对此知之甚少 关于TIM-1：TIM-4通路在同种免疫反应和自身免疫性糖尿病中的作用。初步 本课题组的研究表明，TIM-1：TIM-4通路在同种异体免疫中起着重要作用， 尤其是同种异体反应性T辅助细胞分化和可能调节T细胞的生成/功能。 此外，已经很好地证实，一方面自身反应性Th1细胞和调节性T细胞的平衡 另一方面，细胞和Th2细胞对决定NOD小鼠自身免疫性糖尿病的结局至关重要。 我们的中心假设是TIM-1：TIM-4通路，通过调节Th1/Th2细胞分化和 可能调节T细胞的生成和功能，在同种异体免疫和自身免疫中发挥重要作用 回应和宽容。这项建议的主要目标是界定 TIM-1：TIM-4通路在体内调节免疫反应中的作用 实现持久和可重复的耐受性，并防止反复发生的自身免疫性 异体胰岛移植。在这方面，我们的方法是测试和探索新理性的机制 针对导致同种异体反应性T细胞和自身反应性T细胞沉默的多个通路的联合策略 细胞，并使细胞和/或细胞因子的平衡倾向于细胞和/或细胞因子的调节。 嫁接。在特定的目标1中，我们将研究靶向TIM-1：TIM-4通路在同种异体免疫中的作用 以及同种异体胰岛移植排斥反应模型中的体内自身免疫反应。在具体目标2中，我们将剖析 TIM-1：TIM-4通路在同种异体免疫、自身免疫和耐受中的作用机制 扩增、分化和凋亡。这些研究将利用CD4+和CD8+TCR转基因动物 具有定义的异体(B6背景)和自动(点头背景)特性。MHC四聚体也将 目的：研究TIM-1靶向NOD小鼠自身反应性CD4+和CD8+T细胞的作用机制。 最后，在特定的目标3中，我们将特别关注TIM-1：TIM-4通路在发生中的作用 和/或体内调节性T细胞的功能。Foxp3-GFP敲入小鼠在B6和NOD上的应用 背景，我们将基于最初的初步数据检验这一假设，即TIM-1：TIM-4通路可能 在体内CD4+CD25+调节性T细胞的生成和/或功能中起重要作用。 总体而言，我们的研究应该会获得有用的新数据，这些数据可能会导致开发新的战略来 诱导对同种异体胰岛的耐受，使其转化为甲壳动物和人类。

The T cell immunoglobulin mucin (TIM) family of novel receptor-ligand pairs plays important roles in T cell activation, differentiation and effector/memory function, and in regulation of immune responses in auto- immunity and allergy/asthma. TIM-1 is expressed by activated Th1 and Th2 cells and its expression is sustained preferentially in terminally differentiated Th2 cells. The ligand for TIM-1 is TIM-4, which is predominantly expressed on APCs. Recent studies indicate that TIM-1 may differentially regulate T helper cell (Th1/Th2) differentiation in asthma/allergy, and autoimmune encephalomyelitis. At present, little is known about the role of the TIM-1 :TIM-4 pathway in alloimmune responses and autoimmune diabetes. Preliminary studies from our group indicate that the TIM-1:TIM-4 pathway plays an important role in alloimmunity, particularly alloreactive T helper cell differentiation and possibly regulatory T cell generation/function. Furthermore, it is well established that the balance of autoreactive Th1 cells on one hand and regulatory T cells and Th2 cells on the other is critical in determining the outcome of autoimmune diabetes in NOD mice. Our central hypothesis is that the TIM-1:TIM-4 pathway, by modulating Th1/Th2 cell differentiation and possibly regulatory T cell generation and function, plays an important role in alloimmune and autoimmune responses, and tolerance. The main goal of this proposal is to define the functions and mechanisms of the TIM-1:TIM-4 pathway in regulating immune responses in vivo as a means of developing novel strategies to achieve durable and reproducible tolerance, and preventing the development of recurrent autoimmunity to islet allografts. In that regard, our approach is to test and explore the mechanisms of novel rational combination strategies that target multiple pathways resulting in silencing of alloreactive and autoreactive T cells, and tipping the balance towards regulation by cells and/or cytokines in NOD recipients of islet allo- grafts. In Specific Aim 1 we will investigate the effects of targeting the TIM-1 :TIM-4 pathway on alloimmune and autoimmune responses in vivo in models of islet allograft rejection. In Specific Aim 2 we will dissect the mechanisms of action of TIM-1:TIM-4 pathway in alloimmunity, autoimmunity and tolerance, focusing on T cell expansion, differentiation, and apoptosis. These studies will utilize CD4+ and CD8+ TCR transgenic animals with defined allo- (B6 background) and auto- (NOD background) specificities. MHC tetramers will also be used to study the mechanisms of targeting TIM-1 on autoreactive CD4+ and CD8+ T cells in NOD mice. Finally, in Specific Aim 3 we will focus specifically on the role of TIM-1:TIM-4 pathway in the generation and/or function of regulatory T cells in vivo. Using foxp3-GFP knock-in reporter mice on B6 and NOD backgrounds, we will test the hypothesis, based on initial preliminary data, that the TIM-1:TIM-4 pathwaymay have an important role in the generation and/or function of CD4+CD25+ regulatory T cells in vivo. Overall, our studies shouldyield useful new data that maylead to development of novel strategies to induce tolerance to islet alloarafts to translate to orimates and humans.