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护功能和稳定CDS*内存的机制的理解。因此，这些研究将有助于更好地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，我们最近发现了白介素-2（IL-2）在强大的次级次要（但不是原发性）中的新作用，而不是主要的CDS* T细胞对急性感染的反应。本文提出的实验将探讨IL-2促进功能性CD8+内存的维护的精确机制。具体来说，我们将解决三个主要问题。首先，IL-2对CDS* T细胞的信号何时促进CDS*回忆反应？我们建议三个主要可能性：1）IL-2“程序”在主要响应期间的功能CDS*内存的发展； 2）IL-2保持长寿记忆细胞应对抗原二次相遇的能力；或3）IL-2直接促进了重新收集后CDS* T细胞的二级扩张。为了解决这个问题，我们将开发一个系统，在该系统中，可以在免疫反应的各个阶段诱导IL-2RA表达。第二，IL-2代表一种形式 CD4* T细胞“帮助” CDS*存储器T细胞功能？为了检验这一假设，我们将在只有CD4* T细胞缺乏使IL-2的能力不足的情况下，分析对急性感染的免疫反应。最后，IL-2增强CDS*记忆T细胞的响应能力的机制是什么？我们以前的研究表明，在外围的CD4* CD25*调节T细胞（TR）的数量减少可以挽救IL-2RA缺陷型CDS* T细胞的回忆反应。通过创建一个设置，在使其他细胞群体不受欢迎的同时可以在体内特异性耗尽的设置，我们将测试以下假设：IL-2反对TR介导的CDS*回忆响应的抑制。为了设计更好的疫苗来应对诸如艾滋病毒，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，我们将探讨生长因子白细胞介素-2在增强记忆细胞对第二次接触病原体反应的能力方面的作用。