Understanding and manipulating the T cell contraction phase

了解和操纵 T 细胞收缩期

基本信息

批准号：
7755373
负责人：
J. Lindsay Whitton
金额：
$ 46.9万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7755373
关键词：
Acute Adoptive Transfer Affect Antibodies Antigens Antimetabolites Antiviral Agents Antiviral Response Apoptosis Back Bacterial Infections Biological Brefeldin A CD8-Positive T-Lymphocytes CD8B1 gene Caspase Caspase Inhibitor Cell Death Cell physiology Cells Cellular biology Chronic Color Contracts Cytokine Receptors DNA DNA Vaccines Data Detection Disadvantaged Disease Drops Electronics Endocrine Ensure Event Experimental Models Feedback Feeds Gene Expression Generations Genes Goals Gold Grant Immune response Immunity Immunization Immunocompetent Immunodeficient Mouse Immunology In Vitro Infection Injection of therapeutic agent Interleukin 7 Receptor Kinetics Laboratories Link Literature Lymphocytic choriomeningitis virus Mediating Memory Methods Microbe Modeling Mus Names Natural Killer Cells Normal Cell Phase Phenotype Physiologic pulse Play Population Positioning Attribute Principal Investigator Printing Process Protocols documentation Public Health Publications Publishing Qualifying Reading Reagent Recombinants Recurrence Research Research Personnel Residual state Role Science Signal Transduction Somatic Cell Sorting - Cell Movement Source Survivors System T cell response T memory cell T-Cell Activation T-Cell Proliferation T-Lymphocyte Techniques Testing Time Tissues Transgenic Organisms Vaccination Vaccines Viral Viral Antigens Virus Virus Diseases Wheat Work activated protein C receptor autocrine cytokine exhaust experience fighting human BIRC4 protein in vivo novel strategies paracrine programs receptor receptor expression research study response

项目摘要

DESCRIPTION (provided by applicant): Protective immunity, whether induced by infection or by vaccination, relies on the generation of memory B & T cells in sufficient quantity, and of sufficient quality. In the case of CD8+ T cells - to be studied herein - these memory cells usually represent the few survivors of a dramatic and rapid cull, T cell contraction, in which 90-95% of virus specific CD8+ T cells (in our model, ~50 million cells) are removed over a period of 1-2 weeks. The process of T cell contraction remains poorly-understood, and the overall goal of this proposal is to better characterize the causes and consequences of T cell contraction. The application has the following 4 Specific Aims: 1. To investigate the role of direct IFN3 signaling in regulating CD8+ T cell contraction. IFN3 is a key cytokine. Its receptor is expressed on almost all somatic cells, allowing it to act both as an antiviral effector molecule, and as an immunomodulatory molecule. We have developed a novel approach that allows us to evaluate the direct effects of IFN3 on T cells during virus infection, and we have found that - contrary to much of the published literature - the effects of IFN3 are strongly positive; T cells that are unable to receive IFN3 signals during virus infection are 100-fold less likely to enter the memory pool. In this aim, we propose a detailed analysis of these direct effects. 2. To determine how indirect effects of IFN3 affect T cell contraction. The widespread expression of the IFN3 receptor means that IFN3 also can affect T cell biology indirectly, via a multitude of paths. Some of these indirect effects will be evaluated. 3. To evaluate antigen persistence after acute virus infection is cleared, determine its effects on the quality and quantity of T cells, and analyze the role of IFN3 in these effects. Antigen contact plays an important part in regulating T cell function, and we have developed a new approach that allows us to identify T cells that have recently encountered authentic viral antigen in vivo. We shall ask how recent antigen contact correlates with a variety of T cell phenotypes (proliferative status, expression of cytokine receptors, etc.). 4. To manipulate T cell contraction, and determine the consequences on the quantity and quality of memory cells. Most studies suggest that T cell contraction is relatively random, but I propose that it may be selective, possibly serving to separate the wheat from the chaff. To investigate this, various approaches will be taken to modify the contraction phase, and the quantity and quality of the surviving T cells will be determined.

描述（由申请人提供）：保护性免疫，无论是通过感染还是通过疫苗接种引起的，都依赖于足够数量的记忆B＆T细胞的产生，并且具有足够的质量。对于CD8+ T细胞 - 在本文中进行研究 - 这些记忆细胞通常代表了戏剧性和快速张取T细胞收缩的少数幸存者，其中90-95％的病毒特异性CD8+ T细胞（在我们的模型中，〜〜在1-2周的时间内，将删除5000万个细胞）。 T细胞收缩的过程仍然被理解不足，该提案的总体目标是更好地表征T细胞收缩的原因和后果。该应用具有以下4个特定目的：1。研究直接IFN3信号在调节CD8+ T细胞收缩中的作用。 IFN3是关键的细胞因子。它的受体几乎在所有体细胞上表达，使其既可以充当抗病毒效应分子，又可以作为免疫调节分子。我们开发了一种新型方法，使我们能够评估IFN3在病毒感染过程中对T细胞的直接影响，并且我们发现 - 与许多已发表的文献相反 - IFN3的作用是强烈的；在病毒感染期间无法接收IFN3信号的T细胞进入记忆池的可能性降低了100倍。在此目标中，我们提出了对这些直接影响的详细分析。 2。确定IFN3的间接影响如何影响T细胞收缩。 IFN3受体的广泛表达意味着IFN3也可以通过多种路径间接影响T细胞生物学。这些间接影响中的一些将被评估。 3。要评估急性病毒感染后的抗原持久性，请确定其对T细胞质量和数量的影响，并分析IFN3在这些作用中的作用。抗原接触在调节T细胞功能方面起着重要的作用，我们开发了一种新方法，使我们能够鉴定出在体内遇到正宗病毒抗原的T细胞。我们将询问最近的抗原接触如何与多种T细胞表型（增殖状态，细胞因子受体的表达等）相关。 4。操纵T细胞收缩，并确定对记忆细胞数量和质量的后果。大多数研究表明T细胞收缩是相对随机的，但是我认为它可能是选择性的，可能有助于将小麦与谷壳分开。为了研究这一点，将采用各种方法来修改收缩阶段，并确定幸存的T细胞的数量和质量。