Donor-Reactive Memory Responses and Recall Requirements in Transplantation

项目摘要 阻断T细胞共刺激通路代表了一种有效和高度特异的 预防肾移植后天然抗供者T细胞反应的方法 老鼠、猴子和人。然而，大量研究表明， 受者的供体反应性记忆T细胞构成了有时无法克服的 移植物长期存活和耐受诱导的障碍。尽管有这些发现，但它是 越来越多的人认识到，内部存在着大量的异质性 记忆T细胞群体，包括它们对共刺激的需求 在重新激活期间发出信号。我们发现高NA供体反应性T细胞 前体频率促进记忆性T细胞发育 依赖共刺激信号进行重新激活，并增加了对 共刺激阻断后与供体组织的挑战。因此，在这个 应用，我们假设在T的启动阶段出现的条件 细胞活化导致记忆T细胞亚群分化 二次刺激时对共刺激的要求较低。我们建议 严谨地剖析细胞表面表型、效应器功能和 转录因子在这些供体反应性记忆T细胞中的表达，目的是 阐明影响某些记忆T细胞功能的关键因素 具有协同刺激独立性的特点。 这一问题对移植领域具有临床意义，因为如果共刺激 BLOCKADE要想在临床上成功应用，就必须了解 使记忆T细胞或多或少容易受到共刺激阻断的因素。 该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中需要共刺激。

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.