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核心特征，但许多基本问题仍未得到解答。例如，我们不知道在没有病原体再刺激的情况下，对特定病原体的记忆细胞群能维持多久，也不知道记忆的衰退是如何取决于接触新的病原体的。我们想要这些问题的定量答案，这需要数学模型的发展。模型需要与实验相联系。要做到这一点，需要开发工具来分析实验数据（如CFSE数据），从而使模型得到验证。我们的长期目标是建立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设计疫苗接种方案很重要，例如在人口老龄化的情况下。具体目标1：我们将开发工具来定量描述来自CFSE测量的异质细胞群体的分裂和死亡（这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（在我们之前的拨款中制定）。2. 到目前为止开发的模型在几年的时间尺度上起作用。我们将扩展该模型，以在人类的生命周期中产生更完整的免疫记忆描述。我们将通过开发考虑交叉反应性刺激和复制性衰老的模型来做到这一点。3. 我们将考虑我们的疫苗接种模型的含义，通过考虑人口老龄化中的记忆丧失，最佳促进策略以及多种儿童疫苗的交付顺序。

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.