Understanding and manipulating the T cell contraction phase

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诱导，都依赖于足够数量和足够质量的记忆B和T细胞的产生。在本文将要研究的CD8 + T细胞的情况下，这些记忆细胞通常代表了急剧和快速淘汰的少数幸存者，T细胞收缩，其中90 - 95%的病毒特异性CD8 + T细胞（在我们的模型中，约5000万个细胞）在1 - 2周的时间内被去除。T细胞收缩的过程仍然知之甚少，本提案的总体目标是更好地表征T细胞收缩的原因和后果。该应用程序有以下4个具体目标：1。研究IFN 3直接信号转导在调节CD8 + T细胞收缩中的作用。IFN3是一种关键的细胞因子。它的受体在几乎所有的体细胞上表达，使其既可以作为抗病毒效应分子，也可以作为免疫调节分子。我们已经开发了一种新的方法，使我们能够评估病毒感染期间IFN 3对T细胞的直接影响，我们发现-与大多数已发表的文献相反-IFN 3的影响是强烈的;在病毒感染期间无法接收IFN 3信号的T细胞进入记忆池的可能性降低了100倍。为此，我们提出了这些直接影响的详细分析。2.确定IFN3的间接作用如何影响T细胞收缩。IFN3受体的广泛表达意味着IFN3也可以通过多种途径间接影响T细胞生物学。将对其中一些间接影响进行评估。3.评估急性病毒感染清除后抗原的持续性，确定其对T细胞质量和数量的影响，并分析IFN 3在这些影响中的作用。抗原接触在调节T细胞功能中起着重要作用，我们已经开发出一种新的方法，使我们能够识别最近在体内遇到真实病毒抗原的T细胞。我们将询问最近的抗原接触如何与各种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影响。大多数研究表明，T细胞收缩是相对随机的，但我认为它可能是选择性的，可能有助于区分小麦和谷壳。为了研究这一点，将采取各种方法来修改收缩期，并确定存活T细胞的数量和质量。公共卫生解放：T细胞是免疫反应的重要组成部分。它们帮助我们从许多病毒和细菌感染中恢复，并且它们在疫苗介导的对感染和疾病的免疫中很重要。当微生物进入我们的身体时，我们会产生数百万个这样的T细胞来对抗感染，但是在感染被清除后，绝大多数T细胞都会死亡。在这篇论文中，我研究了T细胞死亡的方式和原因。我还将尝试减少T细胞死亡的数量，希望存活T细胞数量的增加将为我们提供更好的保护，以抵御感染和疾病。

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. PUBLIC HEALTH RELEVENCE:T cells are a vital part of the immune response. They help us recover from many viral and bacterial infections, and they are important in vaccine-mediated immunity to infection and disease. When a microbe enters our body, we produce many millions of these T cells to fight the infection but, after the infection has been cleared, the vast majority of the T cells die. In this grant, I investigate how and why the T cells die. I also will attempt to reduce the amount of T cell death, in the hope that the increased number of surviving T cells will give us increased protection against infection and disease.