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

IL-2 在促进 CD8 记忆 T 细胞反应性中的作用

基本信息

批准号：
7390688
负责人：
Matthew A Williams
金额：
$ 10.8万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7390688
关键词：
Acute Address Antibodies Antibody Formation Antigens Attention Autoimmunity CD4 Positive T Lymphocytes CD8B1 gene Cell Nucleus Cell physiology Cells Chimera organism Communicable Diseases Development Disease Generations Growth Factor HIV Health Immune response Immune system Immunologic Memory Infection Interleukin-2 Left Life Lymphoproliferative Disorders Maintenance Malaria Measles Mediating Memory Mus Names Numbers Pathway interactions Phase Poliomyelitis Population Production Program Development Research Research Personnel Resolution Role Secondary to Signal Transduction Smallpox Source System Systems Analysis T memory cell T-Cell Development T-Lymphocyte Tamoxifen Testing Thymus Gland Time Transgenic Organisms Tuberculosis Vaccination Vaccines Work design in vivo insight long term memory novel pathogen programs recombinase research study response

项目摘要

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.

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性和稳定 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) 在对急性感染产生强有力的次级而非初级 CDS* T 细胞反应中的新作用。本文提出的实验将探索 IL-2 促进功能性 CD8+ 记忆维持的精确机制。具体来说，我们将解决三个主要问题。首先，IL-2 向 CDS* T 细胞发出的信号何时会促进 CDS* 回忆反应？我们提出了三种主要的可能性：1) IL-2 在初级反应期间“编程”功能性 CDS* 记忆的发展； 2) IL-2维持长寿命记忆细胞对二次接触抗原作出反应的能力；或者，3) IL-2 在再次攻击后直接促进 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-2Ra 表达可以在免疫反应的各个阶段被诱导抑制。其次，IL-2 是否代表一种形式？ CD4* T细胞“帮助”维持CDS*记忆T细胞功能？为了检验这个假设，我们将在只有 CD4* T 细胞缺乏产生 IL-2 的能力的环境中分析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？我们之前的研究表明，减少外周 CD4*CD25* 调节性 T 细胞 (TR) 的数量可以挽救 IL-2Ra 缺陷的 CDS* T 细胞的回忆反应。通过创建一个可以在体内特异性耗尽 TR 而同时不影响其他细胞群的环境，我们将检验 IL-2 反对 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产生和维持保护性免疫记忆的方式。在这项工作中，我们将探索生长因子白介素-2 在增强记忆细胞对第二次遇到病原体的反应能力方面的作用。