Mechanism of antigen-induced non-responsiveness in mature CD8+ T cells

根据这项资助之前的工作已经定义了两种形式的外周耐受，可以在CDST细胞中发展。 原始CDST细胞需要三种信号才能完全激活：抗原、共刺激配体(通常为67-1，2)和 IL-12或I型干扰素。在缺乏信号3细胞因子的情况下进行抗原识别会刺激增殖， 但导致效应器功能和记忆的分化程序没有发生，细胞 长期容忍。在目标1下，这些“信号3耐受”细胞的特征将进一步体现在 它们的表型和功能。在目标2下，将进行实验以确定 无响应的基础。初步证据有力地表明，无反应 在缺乏IL-1信号的情况下，关键基因座未能进行染色质重塑所致 12/干扰素-α。当CDST细胞完全激活但进入一种状态时，可能会出现第二种形式的耐受 我们称之为激活诱导无反应性(AINR)，在这种情况下，它们失去产生IL-2的能力 支持继续扩张(无能为力的一种形式)。在目标3下，将进行实验以确定 何时发生从AINR到响应性存储单元的转换，并定义这一转换的机制基础 转换。预计这些研究的结果将有助于更好地了解 诱导CDST细胞外周耐受的基本机制，并提出避免的方法 或逆转对肿瘤和病毒性疾病治疗的耐受性。

Previous work under this grant has defined two forms of peripheral tolerance that can develop in CDST cells. Naive CDST cells require three signals for full activation; antigen, costimulatory ligand (usually 67-1,2) and either IL-12 or Type IIFN. Antigen recognition in the absence of a 'signal 3' cytokine stimulates proliferation, but the differentiation program leading to effector function and memory does not occur, and the cells are tolerant long-term. Under Aim 1, these 'signal 3 tolerant' cells will be further characterized with respect to their phenotype and functional capacity. Under Aim 2, experiments will be done to determine the mechanistic basis for the non-responsiveness. Preliminary evidence strongly suggests that the non-responsiveness results from a failure of critical gene loci to undergo chromatin remodeling in the absence of a signal from IL- 12/IFN-a. A second form of tolerance can occur when CDST cells become fully activated, but enter a state we have termed activation-induced non-responsiveness (AINR) in which they lose the ability to produce IL-2 to support continued expansion (a form of anergy). Under Aim 3, experiments will be done to determine when the conversion from AINR to responsive memory cells occurs, and define the mechanistic basis for this conversion. It is expected that the results of these studies will contribute to a better understanding of the basic mechanisms responsible for inducing peripheral tolerance in CDST cells, and suggest ways of avoiding or reversing tolerance for therapy of tumors and viral diseases.