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

在此资助下，以前的工作已经确定了两种形式的外周耐受性，可以在CDST细胞中发展。 幼稚CDST细胞需要三种信号来完全活化：抗原、共刺激配体（通常为67- 1，2）和 IL-12或IIFN型。在没有“信号3”细胞因子的情况下抗原识别刺激增殖， 但导致效应子功能和记忆的分化程序不会发生， 长期宽容。在目标1下，这些“信号3容忍”小区将进一步表征为： 它们的表型和功能能力。在目标2下，将进行实验以确定 无响应的基础。初步证据强烈表明， 在缺乏来自IL-10的信号的情况下， 12/IFN-a。第二种形式的耐受可能发生在CDST细胞完全激活时，但进入一种状态， 我们称之为激活诱导的无反应性（AINR），即它们失去产生IL-2的能力， 以支持持续的扩张（一种无能量的形式）。根据目标3，将进行实验，以确定 当从AINR到响应存储单元的转换发生时，并定义其机制基础 转换.预计这些研究的结果将有助于更好地了解 CDST细胞中诱导外周耐受的基本机制，并提出避免 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.