Donor-Reactive Memory Responses and Recall Requirements in Transplantation

项目摘要 T细胞共刺激通路的阻断代表了一种有效的和高度特异性的 预防移植后幼稚抗供体T细胞反应的方法 小鼠、猴子和人。然而，许多研究表明， 供体反应性记忆T细胞在受体中的数量， 长期移植物存活和耐受诱导的障碍。尽管有这些发现， 越来越多地认识到，大量的异质性存在于 记忆T细胞群，包括关于它们对共刺激的需求， 在重新激活时发出信号。我们发现高幼稚供体反应性T细胞 前体频率促进记忆T细胞的发育， 依赖于共刺激信号的再激活，以及对 用供体组织激发后的共刺激阻断。所以在这 应用程序，我们假设，条件存在于启动阶段的T 细胞活化导致记忆T细胞群的分化， 在二次刺激期间对共刺激的要求较低。我们建议 严格剖析细胞表面表型、效应子功能和 转录因子在这些供体反应性记忆T细胞中的表达，目的是 阐明了赋予某些记忆T细胞的关键因素， 具有共刺激独立性的特征。 这个问题与移植领域具有临床相关性，因为如果共刺激 阻断是成功地进行临床应用，我们必须了解 使记忆T细胞或多或少易受共刺激阻断的因素。 本提案的目标是调查那些对编程至关重要的参数， 在对移植组织的记忆反应期间需要共刺激。

Project Summary Blockade of T cell costimulatory pathways represents a potent and highly specific method of preventing na¿ve anti-donor T cell responses following transplantation in mouse, monkey, and man. However, numerous studies have shown that the presence of donor-reactive memory T cells in the recipient poses a sometimes insurmountable barrier to long-term graft survival and tolerance induction. Despite these findings, it is increasingly well appreciated that a significant amount of heterogeneity exists within memory T cell populations, including with respect to their requirements for costimulatory signals during reactivation. We have discovered that high na¿ve donor-reactive T cell precursor frequency promotes the development of memory T cells that exhibit increased dependency on costimulatory signals for reactivation, and increased sensitivity to costimulation blockade following challenge with donor tissue. Therefore, in this application, we hypothesize that the conditions present during the priming phase of T cell activation lead to the differentiation of memory T cell populations with a higher or lower requirement for costimulation during secondary stimulation. We propose to rigorously dissect the differences in cell surface phenotype, effector function, and transcription factor expression in these donor-reactive memory T cells, with the goal of elucidating the factors critical for imparting upon some memory T cells their characteristic of costimulation independence. This issue has clinical relevance for the field of transplantation, in that if costimulation blockade is to successfully proceed in clinical application, we must understand the factors that make memory T cells more or less susceptible to costimulation blockade. The goal of this proposal is to investigate those parameters critical for programming the requirement for costimulation during the memory response to transplanted tissue.