Quantitative models of CD8+ T-cell memory

描述（由申请人提供）：虽然免疫记忆是脊椎动物免疫反应的中心特征，但许多基本问题仍在很大程度上没有答案。例如，我们并不真正知道在没有病原体再刺激的情况下，给定病原体的记忆细胞群将维持多久，或者记忆的下降如何取决于暴露于新病原体。我们希望这些问题得到定量的答案，这就需要发展数学模型。模型需要与实验接触。要做到这一点，需要开发工具来分析实验数据（如CFSE数据）的方式，允许模型进行验证。我们的长期目标是建立一个免疫记忆如何工作的定量图像。这种情况对于在各种情况下（如人口老龄化）设计疫苗接种方案非常重要。具体目标1：我们将开发工具来定量描述CFSE测量的异质细胞群的分裂和死亡（它告诉我们细胞的数量以及它们经历的分裂次数）。具体目标2：我们将开发和验证CD8+ T细胞记忆寿命的模型。这一具体目标有三个组成部分。1.我们将通过实验验证我们目前的模型（在我们以前的资助中制定）。2.到目前为止，开发的模型在几年的时间尺度上有效。我们将扩展该模型，以生成对人类寿命期间免疫记忆的更完整描述。我们将通过开发考虑交叉反应刺激和复制衰老的模型来实现这一点。3.我们将通过考虑老龄化人口的记忆丧失、最佳加强策略以及多种儿童疫苗的接种顺序来考虑我们的模型对疫苗接种的影响。

DESCRIPTION (provided by applicant): While immune memory is a central feature of the immune response of vertebrates, many fundamental questions remain largely unanswered. For example we don't really know how long memory cell populations for a given pathogen will be maintained in the absence of restimulation with that pathogen, or how the decline of memory depends on exposure to new pathogens. We would like quantitative answers to these questions, and this requires the development of mathematical models. Models need to be brought into contact with experiments. To do this one needs to develop tools to analyze experimental data (such as CFSE data) in ways which allow the models to be validated. Our long-term goal is to establish a quantitative picture of how immune memory works. Such a picture is important for the design of vaccination protocols in various situations, such as in an aging population. Specific Aim 1: We will develop tools to quantitatively describe division and death of a heterogeneous population of cells from CFSE measurements (which tells us the number of cells as well as the number of divisions they have undergone). Specific Aim 2: We will develop and validate models for the longevity of CD8+ T cell memory. There are three components to this specific aim. 1. We will experimentally validate our current model (formulated in our previous grant). 2. The model developed so far works over the time scale of a few years. We will extend the model to generate a more complete description of immunological memory over the lifespan of humans. We will do this by developing models which consider cross-reactive stimulation and replicative senescence. 3. We will consider the implications of our models for vaccination by considering the loss of memory in an ageing population, the optimal boosting strategy as well as the order of delivery of multiple childhood vaccines.