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，但许多基本问题在很大程度上仍未得到解答。例如，我们并不真正知道在没有某种病原体再刺激的情况下，针对特定病原体的记忆细胞群能够维持多久，或者记忆力的衰退如何取决于接触新病原体。我们想要这些问题的定量答案，这需要数学模型的开发。模型需要与实验联系起来。为此，需要开发工具来分析实验数据（例如 CFSE 数据），从而验证模型。我们的长期目标是建立免疫记忆如何发挥作用的定量图景。这样的情况对于各种情况下（例如人口老龄化）的疫苗接种方案的设计非常重要。具体目标 1：我们将开发工具，通过 CFSE 测量（告诉我们细胞数量以及它们经历的分裂次数）来定量描述异质细胞群的分裂和死亡。具体目标 2：我们将开发并验证 CD8 T 细胞记忆寿命的模型。这一具体目标由三个组成部分组成。 1. 我们将通过实验验证我们当前的模型（在我们之前的资助中制定）。 2. 迄今为止开发的模型在几年的时间范围内有效。我们将扩展该模型，以生成对人类一生中免疫记忆的更完整的描述。我们将通过开发考虑交叉反应刺激和复制衰老的模型来做到这一点。 3. 我们将通过考虑老龄化人群的记忆丧失、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疫苗接种模型的影响。

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.