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加强我们对负责维持功能性和稳定性CDS*存储器的机制的理解。因此，这些研究将有助于合理设计更好的疫苗策略来应对当前的传染病威胁。在这项工作中，我们最近发现了白细胞介素-2 （IL-2）在产生强大的继发性（而不是原发性）CDS* T细胞对急性感染的反应中的新作用。本文提出的实验将探索IL-2促进功能性CD8+记忆维持的确切机制。具体来说，我们将解决三个主要问题。首先，什么时候IL-2信号传导到CDS* T细胞促进CDS*回忆反应？我们提出了三种主要可能性：1)IL-2“程序”在初级反应期间形成功能性CDS*记忆；2) IL-2维持长寿命记忆细胞对抗原二次遭遇的反应能力；3) IL-2直接促进CDS* T细胞在再攻击后的二次扩增。为了解决这个问题，我们将开发一种系统，在该系统中，IL-2Ra的表达可以在免疫反应的各个阶段被诱导抑制。第二，IL-2是否代表一种

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.