The role of IL-2 in promoting CD8 memory T cell responsiveness

描述（由申请人提供）：本申请的长期目标是增强我们对负责维持功能和稳定CDS* 记忆的机制的理解。因此，这些研究将有助于合理设计更好的疫苗策略，以应对当前的传染病威胁。在这项工作中，我们最近发现了一个新的作用，白细胞介素-2（IL-2）在产生强大的二级，但不是主要的，CDS* T细胞反应急性感染。本文提出的实验将探索IL-2促进功能性CD 8+记忆维持的精确机制。具体而言，我们将讨论三个主要问题。首先，IL-2信号传导至CDS* T细胞何时促进CDS* 回忆反应？我们提出了三种主要的可能性：1）IL-2“编程”初级应答期间功能性CDS* 记忆的发展; 2）IL-2维持长寿记忆细胞对与抗原的二次相遇的应答能力;或3）IL-2直接促进再激发后CDS* T细胞的二次扩增。为了解决这个问题，我们将开发一种系统，其中IL-2 Ra表达可以在免疫应答的各个阶段被诱导抑制。第二，IL-2是否代表一种形式的 CD 4 * T细胞“帮助”维持CDS* 记忆T细胞功能？为了验证这个假设，我们将 分析在只有CD 4 * T细胞缺乏制造IL-2能力的情况下对急性感染的免疫反应。最后，IL-2增强CDS* 记忆T细胞反应性的机制是什么？我们以前的研究表明，减少外周中CD 4 * CD 25 * 调节性T细胞（TR）的数量可以挽救IL-2 Ra缺陷型CD 8 * T细胞的回忆反应。通过建立一个TR可以在体内特异性耗尽而其他细胞群不受影响的环境，我们将测试IL-2对抗TR介导的CDS* 回忆反应抑制的假设。为了设计更好的疫苗来应对艾滋病毒、疟疾和结核病等全球健康威胁，我们需要更好地了解我们的免疫系统如何产生和维持保护性免疫记忆。在这项奋进中，我们将探讨生长因子白细胞介素-2在增强记忆细胞对第二次遇到病原体的反应能力中的作用。

DESCRIPTION (provided by applicant): The long-term objectives of this application are to enhance our understanding of the mechanisms responsible for the maintenance of functional and stable CDS* memory. Therefore, these studies will contribute to the rational design of better vaccine strategies to deal with current infectious disease threats. In this effort, we have recently uncovered a novel role for interleukin-2 (IL-2) in the generation of robust secondary, but not primary, CDS* T cell responses to acute infection. The experiments proposed herein will explore the precise mechanisms whereby IL-2 promotes the maintenance of functional CD8+ memory. Specifically, we will address three main questions. First, when does IL-2 signaling to CDS* T cells promote CDS* recall responses? We suggest three main possibilities: 1) IL-2 "programs" the development of functional CDS* memory during the primary response; 2) IL-2 maintains the ability of long-lived memory cells to respond to secondary encounter with antigen; or, 3) IL-2 directly promotes secondary expansion of CDS* T cells following rechallenge. To address this question, we will develop a system in which IL-2Ra expression can be inducibly inhibited at various phases of the immune response. Second, does IL-2 represent a form of CD4* T cell "help" in the maintenance of CDS* memory T cell function? To test this hypothesis, we will analyze immune responses to acute infection in a setting in which only CD4* T cells are deficient in their ability to make IL-2. Lastly, what are the mechanisms by which IL-2 enhances the responsiveness of CDS* memory T cells? Our previous research has suggested that reducing the number of CD4*CD25* regulatory T cells (TR) in the periphery can rescue recall responses by IL-2Ra-deficient CDS* T cells. By creating a setting in which TR can be specifically depleted in vivo while leaving other cell populations untouched, we will test the hypothesis that IL-2 opposes TR-mediated suppression of CDS* recall responses. In order to design better vaccines to deal with global health threats such as HIV, malaria and tuberculosis, we need a better understanding of the way our immune system generates and maintains protective immunological memory. In this endeavor, we will explore the role of the growth factor interleukin-2 in enhancing the ability of memory cells to respond to a second encounter with a pathogen.