从群体水平数据推断适应性免疫应答的分化顺序
Inferring differentiation order in adaptive immune responses from population level data
摘要：
适应性免疫应答的标志是病原体特异性淋巴细胞的增殖，其在它们的觉醒中留下提供持久免疫的长寿命细胞群。一个正在进行的研究主题是在适应性免疫反应期间，这些记忆细胞何时产生。在两项突破性研究中，Buchholz等人（Science，2013）和Gerlach等人（Science，2013）采用了实验方法，该方法允许在单个时间点从体内单个淋巴细胞中鉴定后代，我们称之为克隆数据。通过数学模型的开发、应用和拟合，Buchholz等人（Science，2013）得出结论，如果记忆在扩增阶段产生，则记忆细胞前体在清除原始病原体的效应细胞之前产生。我们试图确定Buchholz等人（Science，2013）中引入的建模方法的一般有效性和功效，通过调整它使其适合于从更容易获得的非克隆表型比例时间过程中进行推断，来快速评估分化网络。我们首先建立了该方法，当拟合Buchholz et al.（Science，2013）本身的非克隆数据时，该方法得出了一致的推论。我们将模型的变体拟合到Badovinac等人（J.Immun.，2007）、Schlub等人（Immun. & Cell Bio.，2010）和Kinjo等人（Nature Commun.，2015）进行必要的简化，以匹配这些论文中不同的报告数据。该模型的推论与Buchholz等人（Science，2013）的推论一致，尽管参数化存在问题。由Kinjo等人（Nature Commun.，2015年），是存储器前体是在扩展阶段之后创建的，这是从Buchholz等人（Science，2013年）中提供的数学方法无法推导出来的。
英文摘要：
A hallmark of the adaptive immune response is the proliferation of pathogen-specific lymphocytes that leave in their wake a long lived population of cells that provide lasting immunity. A subject of ongoing investigation is when during an adaptive immune response those memory cells are produced. In two ground-breaking studies, Buchholz et al. (Science, 2013) and Gerlach et al. (Science, 2013) employed experimental methods that allowed identification of offspring from individual lymphocytes in vivo, which we call clonal data, at a single time point. Through the development, application and fitting of a mathematical model, Buchholz et al. (Science, 2013) concluded that, if memory is produced during the expansion phase, memory cell precursors are made before the effector cells that clear the original pathogen. We sought to determine the general validity and power of the modeling approach introduced in Buchholz et al. (Science, 2013) for quickly evaluating differentiation networks by adapting it to make it suitable for drawing inferences from more readily available non-clonal phenotypic proportion time-courses. We first established the method drew consistent deductions when fit to the non-clonal data in Buchholz et al. (Science, 2013) itself. We fit a variant of the model to data reported in Badovinac et al. (J. Immun., 2007), Schlub et al. (Immun. & Cell Bio., 2010), and Kinjo et al. (Nature Commun., 2015) with necessary simplifications to match different reported data in these papers. The deduction from the model was consistent with that in Buchholz et al. (Science, 2013), albeit with questionable parameterizations. An alternative possibility, supported by the data in Kinjo et al. (Nature Commun., 2015), is that memory precursors are created after the expansion phase, which is a deduction not possible from the mathematical methods provided in Buchholz et al. (Science, 2013).
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