基于模型评估分子内容物的不均匀分配对CD8 T细胞免疫应答中的异质性和分化调节的作用
Model-based assessment of the Role of Uneven Partitioning of Molecular Content on Heterogeneity and Regulation of Differentiation in CD8 T-cell Immune Responses
摘要：
初始CD8 T细胞的活化可导致多个效应子和记忆子组的产生。与活化条件相关的多个参数参与产生与活化细胞的异质分子内容物相关的这种多样性。尽管抗原刺激后幼稚细胞极化和由此产生的不对称分裂已知是异质性和细胞命运调节的主要来源，但随后分裂时分子内容物随机不均匀分配的后果仍不清楚。在这里，我们的目的是研究分子含量异质性的不均匀分配的影响，然后在细胞水平上的免疫反应动力学。为此，我们引入了一个多尺度数学模型的CD8 T细胞免疫反应的淋巴结。在该模型中，细胞被描述为在2D环境中进化和相互作用的代理，而嵌入在每个细胞中的一组微分方程，模拟参与细胞分化的细胞内和细胞外蛋白质的调节。基于单细胞水平的计算机数据分析，我们1表明免疫反应动力学可以解释由细胞分裂时不均匀分配产生的分子含量异质性。特别地，不均匀分配充当细胞分化的调节剂，并诱导表现出拮抗命运的两个共存细胞亚群的出现。我们发现，分子分配的不均匀程度，沿着所有的细胞分裂，影响免疫反应的结果，可以促进记忆细胞的产生。
英文摘要：
Activation of naive CD8 T-cells can lead to the generation of multiple effector and memory subsets. Multiple parameters associated with activation conditions are involved in generating this diversity that is associated with heterogeneous molecular contents of activated cells. Although naive cell polarisation upon antigenic stimulation and the resulting asymmetric division are known to be a major source of heterogeneity and cell fate regulation, the consequences of stochastic uneven partitioning of molecular content upon subsequent divisions remain unclear yet. Here we aim at studying the impact of uneven partitioning on molecular-content heterogeneity and then on the immune response dynamics at the cellular level. To do so, we introduce a multiscale mathematical model of the CD8 T-cell immune response in the lymph node. In the model, cells are described as agents evolving and interacting in a 2D environment while a set of differential equations, embedded in each cell, models the regulation of intra and extracellular proteins involved in cell differentiation. Based on the analysis of in silico data at the single cell level, we 1 show that immune response dynamics can be explained by the molecular-content heterogeneity generated by uneven partitioning at cell division. In particular, uneven partitioning acts as a regulator of cell differentiation and induces the emergence of two coexisting sub-populations of cells exhibiting antagonistic fates. We show that the degree of unevenness of molecular partitioning, along all cell divisions, affects the outcome of the immune response and can promote the generation of memory cells.
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